Methods using phenethanolamine derivatives for treatment of respiratory diseases

ABSTRACT

The present invention relates to novel compounds of Formula (I), to a process for their manufacture, to pharmaceutical compositions containing them, and to their use in therapy, in particular their use in the prophylaxis and treatment of respiratory diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of Ser. No. 10/467,733filed Feb. 9, 2004, now U.S. Pat. No. 7,135,600 which was filed under 35U.S.C. § 371 as the United States National Phase Application ofInternational Application No. PCT/EP02/01387 filed Feb. 11, 2002claiming priority from Great Britain Application Nos. 0103630.0 and0126998.4, filed Feb. 14, 2001 and Nov. 9, 2001 respectively.

The present invention is concerned with phenethanolamine derivatives,processes for their preparation, compositions containing them and theiruse in medicine, particularly in the prophylaxis and treatment ofrespiratory diseases.

Certain phenethanolamine compounds are known in the art as havingselective stimulant action at β₂-adrenoreceptors and therefore havingutility in the treatment of bronchial asthma and related disorders. ThusGB 2 140 800 describes phenethanolamine compounds including4-hydroxy-α¹-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol1-hydroxy-2-naphthalenecarboxylate (salmeterol xinafoate) which is nowused clinically in the treatment of such medical conditions.

Although salmeterol and the other commercially availableβ₂-adrenoreceptor agonists are effective bronchodilators, the maximumduration of action is 12 hours, hence twice daily dosing is oftenrequired. There is therefore a clinical need for compounds having potentand selective stimulant action at β₂₋adrenoreceptors and having anadvantageous profile of action.

According to the present invention, there is provided a compound offormula (I)

or a salt, solvate, or physiologically functional derivative thereof,wherein:

-   m is an integer of from 2 to 8;-   n is an integer of from 3 to 11, preferably from 3 to 7;-   with the proviso that m+n is 5 to 19, preferably 5 to 12;-   R¹ is —XSO₂NR⁶R⁷-   wherein X is —(CH₂)_(p)— or C₂₋₆ alkenylene;-   R⁶ and R⁷ are independently selected from hydrogen, C₁₋₆alkyl,-   C₃₋₇cycloalkyl, C(O)NR⁸R⁹, phenyl, and phenyl(C₁₋₄alkyl)-,-   or R⁶ and R⁷, together with the nitrogen to which they are bonded,    form a 5-, 6-, or 7-membered nitrogen containing ring,-   and R⁶ and R⁷ are each optionally substituted by one or two groups    selected from halo, C₁₋₄alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,    hydroxy-substituted C₁₋₆alkoxy, —CO₂R⁸, —SO₂NR⁸R⁹, —CONR⁸R⁹,    —NR⁸C(O)R⁹, or a 5-, 6- or 7-membered heterocylic ring;-   R⁸ and R⁹ are independently selected from hydrogen, C₁₋₆alkyl,-   C₃₋₆cycloalkyl, phenyl, and phenyl(C₁₋₄alkyl)-; and-   p is an integer of from 0 to 6, preferably from 0 to 4;-   R² and R³ are independently selected from hydrogen, C₁₋₆alkyl,    C₁₋₆alkoxy, halo, phenyl, and C₁₋₆haloalkyl; and-   R⁴ and R⁵ are independently selected from hydrogen and C₁₋₄alkyl    with the proviso that the total number of carbon atoms in R⁴ and R⁵    is not more than 4.

In the compounds of formula (I) the group R¹ is preferably attached tothe meta-position relative to the —O—(CH₂)_(n)— link.

R¹ preferably represents —SO₂NR⁶R⁷ wherein R⁶ and R⁷ are independentlyselected from hydrogen and C₁₋₆alkyl, more preferably R¹ is —SO₂NH₂.

R⁴ and R⁵ are preferably independently selected from hydrogen andmethyl, more preferably R⁴ and R⁵ are both hydrogen.

m is suitably 4, 5, or 6, and n is suitably 3, 4, 5 or 6. Preferably mis 5 or 6 and n is 3 or 4, such that m+n is 8, 9 or 10, preferably 9.

According to a preferred aspect of the invention, there is provided acompound of formula (Ia)

or a salt, solvate, or physiologically functional derivative thereof,wherein

-   R¹ is as defined above for formula (I).

According to a further preferred aspect of the invention, there isprovided a compound of formula (Ib)

or a salt, solvate, or physiologically functional derivative thereof,wherein

-   R¹ is as defined above for formula (I).

In the compounds of formulae (Ia) and (Ib), the group R¹ is preferablyattached to the meta-position relative to the —O—(CH₂)_(n)—, —O—(CH₂)₄—or —O—(CH₂)₃— link respectively.

In the compounds of formulae (Ia) and (Ib), R¹ is preferably —SO₂NR⁶R⁷wherein R⁶ and R⁷ are independently selected from hydrogen andC₁₋₆alkyl, more preferably R¹ is —SO₂NH₂.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.

FIG. 1 illustrates the X-Ray Powder Diffraction (XRPD) pattern of theproduct referred to in Example 48(ii).

FIG. 2 illustrates the X-Ray Powder Diffraction (XRPD) pattern of theproduct referred to in Example 48(iii).

FIG. 3 illustrates the X-Ray Powder Diffraction (XRPD) pattern of theproduct referred to in Example 48(iv).

FIG. 4 illustrates the X-Ray Powder Diffraction (XRPD) pattern of theproduct referred to in Example 48(v).

FIG. 5 illustrates the X-Ray Powder Diffraction (XRFD) pattern of theproduct referred to in Example 48(vi).

Preferred compounds of the invention include:

-   3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide;-   4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide;-   2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide;-   3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N-methylbenzenesulfonamide;-   2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(morpholin-4-ylsulfonyl)-phenyl]butoxy}hexyl)amino]ethyl}phenol;-   3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N,N-dimethylbenzenesulfonamide;-   3-(4-{[6    ({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N-isopropylbenzenesulfonamide;-   N-(tert-Butyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(piperidin-1-ylsulfonyl)phenyl]-butoxy}hexyl)amino]ethyl}phenol;-   1-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-hexyl]oxy}butyl)phenyl]methanesulfonamide;-   3-(5-{[5-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)pentyl]oxy}pentyl)benzenesulfonamide;-   3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide;-   3-{6-[4-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)butoxy]hexyl}benzenesulfonamide;-   4-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]butane-1-sulfonamide;-   3-(5-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}pentyl)benzenesulfonamide;-   3-(6-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}hexyl)benzenesulfonamide;-   3-(3-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}propyl)benzenesulfonamide;-   3-(4-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}butyl)benzenesulfonamide;-   1-[2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]methanesulfonamide;-   1-[4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]methanesulfonamide;-   N-[3-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   N-Benzyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   4-{(1R)-2-[(6-{4-[3-({[(Ethylamino)carbonyl]amino}sulfonyl)phenyl]butoxy}-hexyl)amino]-1-hydroxyethyl}-1-hydroxy-2-(hydroxymethyl)benzene;-   3-(4-{[6-({2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   N-[4-({[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]sulfonyl}amino)phenyl]acetamide-   N-Cyclobutyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   N-Cyclohexyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N-(2-morpholin-4-ylethyl)benzenesulfonamide;-   N-[2-(2-Hydroxyethoxy)ethyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   N-(4-Fluorophenyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   N-[4-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(piperazin-1-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethyl}phenol;-   3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N-(1-methyl-1-phenylethyl)benzenesulfonamide;-   5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-ethyl}amino)hexyl]oxy}butyl)-2-methoxybenzenesulfonamide;-   3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-5-pentylbenzenesulfonamide;-   (E)-2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]-N-methylethenesulfonamide;-   2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]ethanesulfonamide;-   5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)[1,1′-biphenyl]-3-sulfonamide;-   3-Fluoro-5-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;-   5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-3-trifluoromethylbenzenesulfonamide;-   3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-5-methylbenzenesulfonamide    acetate;-   N-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}glycine;-   N²-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}glycinamide;    and salts, solvates, and physiologically functional derivatives    thereof.

Particularly preferred compounds of the invention include:

-   3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide;-   3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide;-   3-(4-{[6-({(2R/S)-2-Hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide;-   3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide;-   3-(3-{[7-({(2S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide;-   3-(3-{[7-({(2R/S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-35    amino)heptyl]oxy}propyl)benzenesulfonamide;    and salts, solvates, and physiologically functional derivatives    thereof.

Of these compounds,3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)-phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideand3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamideare especially preferred.

In the definition of R¹ where ‘R⁶ and R⁷ together with the nitrogen atomto which they are bonded, form a 5-, 6-, or 7-membered nitrogencontaining ring’, the term “5-, 6-, or 7-membered nitrogen containingring” means a 5-, 6-, or 7-membered saturated or unsaturated ring whichincludes the sulfonamide nitrogen atom and optionally 1 or 2 otherheteroatoms independently selected from nitrogen, sulphur, and oxygen.Suitable examples of such a ring include piperidinyl, morpholinyl, andpiperazinyl.

In the definition of R¹, specifically the optional substituents on R⁶and R⁷, the term “5-, 6-, or 7-membered heterocyclic ring” means a 5-,6-, or 7-membered fully or partially saturated or unsaturated ring whichincludes 1, 2, 3 or 4 heteroatoms independently selected from nitrogen,sulphur, and oxygen. Suitable examples of such a ring include pyrrolyl,furyl, thienyl, pyridinyl, pyrazinyl, pyridazinyl, imidazolyl,tetrazolyl, tetrahydrofuranyl, oxazolyl, thiazolyl, thiadiazolyl,piperidinyl, morpholinyl, and piperazinyl.

In the definition of X, the term “alkenylene” includes both cis andtrans structures. Suitable examples of alkenylene groups include—CH═CH—.

The compounds of formulae (I), (Ia) and (Ib) include an asymmetriccentre, namely the carbon atom of the

group. The present invention includes both (S) and (R) enantiomerseither in substantially pure form or admixed in any proportions.

Similarly, where R⁴ and R⁵ are different groups, the carbon atom towhich they are attached is an asymmetric centre and the presentinvention includes both (S) and (R) enantiomers at this centre either insubstantially pure form or admixed in any proportions.

Thus the compounds of formulae (I), (Ia) and (Ib) include allenantiomers and diastereoisomers as well as mixtures thereof in anyproportions.

Salts and solvates of compounds of formulae (I), (Ia) and (Ib) which aresuitable for use in medicine are those wherein the counterion orassociated solvent is pharmaceutically acceptable. However, salts andsolvates having non-pharmaceutically acceptable counterions orassociated solvents are within the scope of the present invention, forexample, for use as intermediates in the preparation of other compoundsof formulae (I), (Ia) and (Ib) and their pharmaceutically acceptablesalts, solvates, and physiologically functional derivatives.

By the term “physiologically functional derivative” is meant a chemicalderivative of a compound of formula (I), (Ia) or (Ib) having the samephysiological function as the parent compound of formula (I), (Ia) or(Ib), for example, by being convertible in the body thereto.

According to the present invention, examples of physiologicallyfunctional derivatives include esters.

Suitable salts according to the invention include those formed with bothorganic and inorganic acids or bases. Pharmaceutically acceptable acidaddition salts include those formed from hydrochloric, hydrobromic,sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic,oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic,methanesulphonic, ethanesulphonic, arylsulphonic (for examplep-toluenesulphonic, benzenesulphonic, naphthalenesulphonic ornaphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic,cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy orhalo substituted cinnamic, including 4-methyl and 4-methoxycinnamicacid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or3-hydroxy-2-naphthoic), naphthaleneacrylic (for examplenaphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (forexample 1,4-benzenediacrylic) and isethionic acids. Pharmaceuticallyacceptable base salts include ammonium salts, alkali metal salts such asthose of sodium and potassium, alkaline earth metal salts such as thoseof calcium and magnesium and salts with organic bases such asdicyclohexyl amine and N-methyl-D-glucamine.

Advantageously, preferred compounds of the invention such as3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideand3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamideare provided in the form of a crystalline salt, for example selectedfrom those exemplified in the experimental section below. Saidcrystalline salts have favourable physical properties such as lowhygroscopicity and/or improved stability. Particularly preferred saltsinclude the cinnamate, 4-methoxycinnamate, 4-methylcinnamate,naphthalenepropenoate and 4-phenylcinnamate salts.

Pharmaceutically acceptable esters of the compounds of formulae (I),(Ia) and (Ib) may have a hydroxyl group converted to a C₁₋₆alkyl, aryl,aryl C₁₋₆ alkyl, or amino acid ester.

As mentioned above, the compounds of formulae (I), (Ia) and (Ib) areselective β₂-adrenoreceptor agonists as demonstrated using functional orreporter gene readout from cell lines transfected with humanbeta-adrenoreceptors as described below. Compounds according to thepresent invention also have the potential to combine long duration ofeffect with rapid onset of action. Furthermore, certain compounds haveshown an improved therapeutic index in animal models relative toexisting long-acting β₂-agonist bronchodilators. As such, compounds ofthe invention may be suitable for once-daily administration.

Compounds of formulae (I), (Ia) and (Ib) and their pharmaceuticallyacceptable salts, solvates, and physiologically functional derivativeshave use in the prophylaxis and treatment of clinical conditions forwhich a selective β₂-adrenoreceptor agonist is indicated. Suchconditions include diseases associated with reversible airwaysobstruction such as asthma, chronic obstructive pulmonary diseases(COPD) (e.g. chronic and wheezy bronchitis, emphysema), respiratorytract infection and upper respiratory tract disease (e.g. rhinitis,including seasonal and allergic rhinitis).

Other conditions which may be treated include premature labour,depression, congestive heart failure, skin diseases (e.g. inflammatory,allergic, psoriatic, and proliferative skin diseases), conditions wherelowering peptic acidity is desirable (e.g. peptic and gastriculceration) and muscle wasting disease.

Accordingly, the present invention provides a method for the prophylaxisor treatment of a clinical condition in a mammal, such as a human, forwhich a selective β₂-adrenoreceptor agonist is indicated, whichcomprises administration of a therapeutically effective amount of acompound of formula (I), (Ia) or (Ib), or a pharmaceutically acceptablesalt, solvate, or physiologically functional derivative thereof. Inparticular, the present invention provides such a method for theprophylaxis or treatment of a disease associated with reversible airwaysobstruction such as asthma, chronic obstructive pulmonary disease(COPD), respiratory tract infection or upper respiratory tract disease.In a further aspect the present invention provides such a method for theprophylaxis or treatment of a clinical condition selected from prematurelabour, depression, congestive heart failure, skin diseases (e.g.inflammatory, allergic, psoriatic, and proliferative skin diseases),conditions where lowering peptic acidity is desirable (e.g. peptic andgastric ulceration) or muscle wasting disease.

In the alternative, there is also provided a compound of formula (I),(Ia) or (Ib) or a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof for use in medicaltherapy, particularly, for use in the prophylaxis or treatment of aclinical condition in a mammal, such as a human, for which a selectiveβ₂-adrenoreceptor agonist is indicated. In particular, there is provideda compound of formula (I), (Ia) or (Ib) or a pharmaceutically acceptablesalt, solvate, or physiologically functional derivative thereof for theprophylaxis or treatment of a disease associated with reversible airwaysobstruction such as asthma, chronic obstructive pulmonary disease(COPD), respiratory tract infection or upper respiratory tract disease.In a further aspect, there is provided a compound of formula (I), (Ia)or (Ib) or a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof for the prophylaxis ortreatment of a clinical condition selected from premature labour,depression, congestive heart failure, skin diseases (e.g. inflammatory,allergic, psoriatic, and proliferative skin diseases), conditions wherelowering peptic acidity is desirable (e.g. peptic and gastriculceration) or muscle wasting disease.

The present invention also provides the use of a compound of formula(I), (Ia) or (Ib), or a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof in the manufacture of amedicament for the prophylaxis or treatment of a clinical condition forwhich a selective β₂-adrenoreceptor agonist is indicated, for example adisease associated with reversible airways obstruction such as asthma,chronic obstructive pulmonary disease (COPD), respiratory tractinfection or upper respiratory tract disease. In a further aspect, thereis provided a compound of formula (I), (Ia) or (Ib), or apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof in the manufacture of a medicament for theprophylaxis or treatment of a clinical condition selected from prematurelabour, depression, congestive heart failure, skin diseases (e.g.inflammatory, allergic, psoriatic, and proliferative skin diseases),conditions where lowering peptic acidity is desirable (e.g. peptic andgastric ulceration) and muscle wasting disease.

The amount of a compound of formula (I), (Ia) or (Ib), or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof which is required to achieve a therapeutic effectwill, of course, vary with the particular compound, the route ofadministration, the subject under treatment, and the particular disorderor disease being treated. The compounds of the invention may beadministered by inhalation at a dose of from 0.0005 mg to 10 mg,preferably 0.005 mg to 0.5 mg. The dose range for adult humans isgenerally from 0.0005 mg to 100 mg per day and preferably 0.01 mg to 1mg per day.

While it is possible for the compound of formula (I), (Ia) or (Ib), or apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof to be administered alone, it is preferable to presentit as a pharmaceutical formulation.

Accordingly, the present invention further provides a pharmaceuticalformulation comprising a compound of formula (I), (Ia) or (Ib) or apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof, and a pharmaceutically acceptable carrier orexcipient, and optionally one or more other therapeutic ingredients.

Hereinafter, the term “active ingredient” means a compound of formula(I), (Ia) or (Ib), or a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), inhalation (including fine particle dusts or mistswhich may be generated by means of various types of metered dosepressurised aerosols, nebulisers or insufflators), rectal and topical(including dermal, buccal, sublingual and intraocular) administrationalthough the most suitable route may depend upon for example thecondition and disorder of the recipient. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing the active ingredient into association with thecarrier which constitutes one or more accessory ingredients. In generalthe formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example saline or water-for-injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of for examplegelatine, or blisters of for example laminated aluminium foil, for usein an inhaler or insufflator. Formulations generally contain a powdermix for inhalation of the compound of the invention and a suitablepowder base (carrier substance) such as lactose or starch. Use oflactose is preferred. Each capsule or cartridge may generally containbetween 20 μg-10 mg of the compound of formula (I) optionally incombination with another therapeutically active ingredient.Alternatively, the compound of the invention may be presented withoutexcipients. Packaging of the formulation may be suitable for unit doseor multi-dose delivery. In the case of multi-dose delivery, theformulation can be pre-metered (eg as in Diskus, see GB 2242134 orDiskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg asin Turbuhaler, see EP 69715). An example of a unit-dose device isRotahaler (see GB 2064336). The Diskus inhalation device comprises anelongate strip formed from a base sheet having a plurality of recessesspaced along its length and a lid sheet hermetically but peelably sealedthereto to define a plurality of containers, each container havingtherein an inhalable formulation containing a compound of formula (I)preferably combined with lactose. Preferably, the strip is sufficientlyflexible to be wound into a roll. The lid sheet and base sheet willpreferably have leading end portions which are not sealed to one anotherand at least one of the said leading end portions is constructed to beattached to a winding means. Also, preferably the hermetic seal betweenthe base and lid sheets extends over their whole width. The lid sheetmay preferably be peeled from the base sheet in a longitudinal directionfrom a first end of the said base sheet.

Spray compositions for topical delivery to the lung by inhalation mayfor example be formulated as aqueous solutions or suspensions or asaerosols delivered from pressurised packs, such as a metered doseinhaler, with the use of a suitable liquefied propellant. Aerosolcompositions suitable for inhalation can be either a suspension or asolution and generally contain the compound of formula (I) optionally incombination with another therapeutically active ingredient and asuitable propellant such as a fluorocarbon or hydrogen-containingchlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes,e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxideor other suitable gas may also be used as propellant. The aerosolcomposition may be excipient free or may optionally contain additionalformulation excipients well known in the art such as surfactants egoleic acid or lecithin and cosolvents eg ethanol. Pressurisedformulations will generally be retained in a canister (eg an aluminiumcanister) closed with a valve (eg a metering valve) and fitted into anactuator provided with a mouthpiece.

Medicaments for administration by inhalation desirably have a controlledparticle size. The optimum particle size for inhalation into thebronchial system is usually 1-10 μm, preferably 2-5 μm. Particles havinga size above 20 μm are generally too large when inhaled to reach thesmall airways. To achieve these particle sizes the particles of theactive ingredient as produced may be size reduced by conventional meanseg by micronisation. The desired fraction may be separated out by airclassification or sieving. Preferably, the particles will becrystalline. When an excipient such as lactose is employed, generally,the particle size of the excipient will be much greater than the inhaledmedicament within the present invention. When the excipient is lactoseit will typically be present as milled lactose, wherein not more than85% of lactose particles will have a MMD of 60-90 μm and not less than15% will have a MMD of less than 15 μm.

Intranasal sprays may be formulated with aqueous or non-aqueous vehicleswith the addition of agents such as thickening agents, buffer salts oracid or alkali to adjust the pH, isotonicity adjusting agents oranti-oxidants.

Solutions for inhalation by nebulation may be formulated with an aqueousvehicle with the addition of agents such as acid or alkali, buffersalts, isotonicity adjusting agents or antimicrobials. They may besterilised by filtration or heating in an autoclave, or presented as anon-sterile product.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured basis such as sucrose and acacia ortragacanth, and pastilles comprising the active ingredient in a basissuch as gelatin and glycerin or sucrose an acacia.

Preferred unit dosage formulations are those containing an effectivedose, as hereinbefore recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavouring agents.

The compounds and pharmaceutical formulations according to the inventionmay be used in combination with or include one or more other therapeuticagents, for example selected from anti-inflammatory agents,anticholinergic agents (particularly an M₁, M₂, M₁/M₂ or M₃ receptorantagonist), other β₂-adrenoreceptor agonists, antiinfective agents(e.g. antibiotics, antivirals), or antihistamines. The invention thusprovides, in a further aspect, a combination comprising a compound offormula (I) or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof together with one or moreother therapeutically active agents, for example selected from ananti-inflammatory agent (for example a corticosteroid or an NSAID), ananticholinergic agent, another β₂-adrenoreceptor agonist, anantiinfective agent (e.g. an antibiotic or an antiviral), or anantihistamine. Preferred are combinations comprising a compound offormula (I) or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof together with acorticosteroid, and/or an anticholinergic, and/or a PDE-4 inhibitor.Preferred combinations are those comprising one or two other therapeuticagents.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredient(s) may be used in the form of salts,(e.g. as alkali metal or amine salts or as acid addition salts), orprodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g.hydrates) to optimise the activity and/or stability and/or physicalcharacteristics (e.g. solubility) of the therapeutic ingredient. It willbe clear also that where appropriate, the therapeutic ingredients may beused in optically pure form.

Suitable anti-inflammatory agents include corticosteroids and NSAIDs.Suitable corticosteroids which may be used in combination with thecompounds of the invention are those oral and inhaled corticosteroidsand their pro-drugs which have anti-inflammatory activity. Examplesinclude methyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl)ester, beclomethasone esters (e.g.the 17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (e.g. the furoate ester), triamcinoloneacetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541,and ST-126. Preferred corticosteroids include fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, more preferably6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitorsor mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors ofleukotriene synthesis, iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists and adenosine receptor agonistsor antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g.chemokine antagonists) or inhibitors of cytokine synthesis. Suitableother β₂-adrenoreceptor agonists include salmeterol (e.g. as thexinafoate), salbutamol (e.g. as the sulphate or the free base),formoterol (e.g. as the fumarate), fenoterol or terbutaline and saltsthereof.

Of particular interest is use of the compound of formula (I) incombination with a phosphodiesterase 4 (PDE4) inhibitor or a mixedPDE3/PDE4 inhibitor. The PDE4-specific inhibitor useful in this aspectof the invention may be any compound that is known to inhibit the PDE4enzyme or which is discovered to act as a PDE4 inhibitor, and which areonly PDE4 inhibitors, not compounds which inhibit other members of thePDE family as well as PDE4. Generally it is preferred to use a PDE4inhibitor which has an IC₅₀ ratio of about 0.1 or greater as regards theIC₅₀ for the PDE4 catalytic form which binds rolipram with a highaffinity divided by the IC₅₀ for the form which binds rolipram with alow affinity. For the purposes of this disclosure, the cAMP catalyticsite which binds R and S rolipram with a low affinity is denominated the“low affinity” binding site (LPDE 4) and the other form of thiscatalytic site which binds rolipram with a high affinity is denominatedthe “high affinity” binding site (HPDE 4). This term “HPDE4” should notbe confused with the term “hPDE4” which is used to denote human PDE4.

Initial experiments may be conducted to establish and validate a[³H]-rolipram binding assay. Details of this work are given in theBinding Assays described in detail below.

Phosphodiesterase and Rolipram Binding Assays

Assay Method 1A

Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) wasdetermined to exist primarily in the low affinity form. Hence, theactivity of test compounds against the low affinity form of PDE4 can beassessed using standard assays for PDE4 catalytic activity employing 1μM [³H]cAMP as a substrate (Torphy et al., J. of Biol. Chem., Vol. 267,No. 3 pp 1798-1804, 1992). Rat brain high speed supernatants were usedas a source of protein and both enantiomers of [³H]-rolipram wereprepared to a specific activity of 25.6 Ci/mmol. Standard assayconditions were modified from the published procedure to be identical tothe PDE assay conditions, except for the last of the cAMP: 50 mM TrisHCl (pH 7.5), 5 mM MgCl₂, 50 μM 5′-AMP and 1 nM of [³H]-rolipram (Torphyet al., J. of Biol. Chem., Vol. 267, No. 3 pp 1798-1804, 1992). Theassay was run for 1 hour at 30° C. The reaction was terminated and boundligand was separated from free ligand using a Brandel cell harvester.Competition for the high affinity binding site was assessed underconditions that were identical to those used for measuring low affinityPDE activity, expect that [³H]-cAMP was not present.

Assay Method 1B

Measurement of Phosphodiesterase Activity

PDE activity was assayed using a [³H]cAMP SPA or [³H]cGMP SPA enzymeassay as described by the supplier (Amersham Life Sciences). Thereactions were conducted in 96-well plates at room temperature, in 0.1ml of reaction buffer containing (final concentrations): 50 mM Tris-HCl,pH 7.5, 8.3 mM MgCl₂, 1.7 mM EGTA, [³H]cAMP or [³H]cGMP (approximately2000 dpm/pmol), enzyme and various concentrations of the inhibitors. Theassay was allowed to proceed for 1 hr and was terminated by adding 50 μlof SPA yttrium silicate beads in the presence of zinc sulfate. Theplates were shaken and allowed to stand at room temperature for 20 min.Radiolabeled product formation was assessed by scintillationspectrometry.

[³H]R-Rolipram Binding Assay

The [³H]R-rolipram binding assay was performed by modification of themethod of Schneider and co-workers, see Nicholson, et al., TrendsPharmacol. Sci., Vol. 12, pp. 19-27 (1991) and McHale et al., Mol.Pharmacol., Vol. 39, 109-113 (1991). R-Rolipram binds to the catalyticsite of PDE4 see Torphy et al., Mol. Pharmacol., Vol. 39, pp. 376-384(1991). Consequently, competition for [³H]R-rolipram binding provides anindependent confirmation of the PDE4 inhibitor potencies of unlabeledcompetitors. The assay was performed at 30° C. for 1 hr in 0.5 μl buffercontaining (final concentrations): 50 mM Tris-HCl, pH 7.5, 5 mM MgCl₂,0.05% bovine serum albumin, 2 nM [³H]R-rolipram (5.7×104 dpm/pmol) andvarious concentrations of non-radiolabeled inhibitors. The reaction wasstopped by the addition of 2.5 ml of ice-cold reaction buffer (without[³H]—R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester)through Whatman GF/B filters that had been soaked in 0.3%polyethylenimine. The filters were washed with an additional 7.5 ml ofcold buffer, dried, and counted via liquid scintillation spectrometry.The preferred PDE4 inhibitors of use in this invention will be thosecompounds which have a salutary therapeutic ratio, i.e., compounds whichpreferentially inhibit cAMP catalytic activity where the enzyme is inthe form that binds rolipram with a low affinity, thereby reducing theside effects which apparently are linked to inhibiting the form whichbinds rolipram with a high affinity. Another way to state this is thatthe preferred compounds will have an IC₅₀ ratio of about 0.1 or greateras regards the IC₅₀ for the PDE4 catalytic form which binds rolipramwith a high affinity divided by the IC₅₀ for the form which bindsrolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4inhibitor has an IC₅₀ ratio of about 0.1 or greater; said ratio is theratio of the IC₅₀ value for competing with the binding of 1 nM of[³H]R-rolipram to a form of PDE4 which binds rolipram with a highaffinity over the IC₅₀ value for inhibiting the PDE4 catalytic activityof a form which binds rolipram with a low affinity using 1 μM [³H]-cAMPas the substrate.

Examples of useful PDE4 inhibitors are:

-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone;-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone;-   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone;-   cis    4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic    acid];-   cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];-   (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate;    and-   (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate.

Most preferred are those PDE4 inhibitors which have an IC₅₀ ratio ofgreater than 0.5, and particularly those compounds having a ratio ofgreater than 1.0. Preferred compounds are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];these are examples of compounds which bind preferentially to the lowaffinity binding site and which have an IC₅₀ ratio of 0.1 or greater.

Other compounds of interest include:

Compounds set out in U.S. Pat. No. 5,552,438 issued 3 Sep. 1996; thispatent and the compounds it discloses are incorporated herein in full byreference. The compound of particular interest, which is disclosed inU.S. Pat. No. 5,552,438, iscis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomalast) and its salts, esters, pro-drugs orphysical forms;

AWD-12-281 from Asta Medica (Hofgen, N. et al. 15th EFMC Int Symp MedChem (September 6-10, Edinburgh) 1998, Abst P. 98; CAS reference No.247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM);D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; abenzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34from Kyowa Hakko; V-11294A from Napp (Landells, L. J. et al. Eur Resp J[Annu Cong Eur Resp Soc (September 19-23, Geneva) 1998] 1998, 12 (Suppl.28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and apthalazinone (WO99/47505, the disclosure of which is hereby incorporatedby reference) from Byk-Gulden; Pumafentrine,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vemalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 162), andT2585.

Other possible PDE-4 and mixed PDE3/PDE4 inhibitors include those listedin WO01/13953, the disclosure of which is hereby incorporated byreference.

Suitable anticholinergic agents are those compounds that act asantagonists at the muscarinic receptor, in particular those compoundswhich are antagonists of the M₁ and M₂ receptors.

Exemplary compounds include the alkaloids of the belladonna plants asillustrated by the likes of atropine, scopolamine, homatropine,hyoscyamine; these compounds are normally administered as a salt, beingtertiary amines. These drugs, particularly the salt forms, are readilyavailable from a number of commercial sources or can be made or preparedfrom literature data via, to wit:

-   Atropine—CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropine    sulfate—CAS-5908-99-6; atropine oxide—CAS-4438-22-6 or its HCl    salt—CAS-4574-60-1 and methylatropine nitrate—CAS-52-88-0.

Homatropine—CAS-87-00-3, hydrobromide salt—CAS-51-56-9, methylbromidesalt—CAS-80-49-9.

Hyoscyamine (d,l)—CAS-101-31-5, hydrobromide salt—CAS-306-03-6 andsulfate salt—CAS-6835-16-1.

Scopolamine—CAS-51-34-3, hydrobromide salt—CAS-6533-68-2, methylbromidesalt—CAS-155-41-9.

Preferred anticholinergics include ipratropium (e.g. as the bromide),sold under the name Atrovent, oxitropium (e.g. as the bromide) andtiotropium (e.g. as the bromide) (CAS-139404-48-1). Also of interestare: methantheline (CAS-53-46-3), propantheline bromide (CAS-50-34-9),anisotropine methyl bromide or Valpin 50 (CAS-80-50-2), clidiniumbromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamideiodide (CAS-71-81-8), mepenzolate bromide (U.S. Pat. No. 2,918,408),tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocycliummethylsulfate (Tral, CAS-115-63-9). See also cyclopentolatehydrochloride (CAS-5870-29-1), tropicamide (CAS-1508-75-4),trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine(CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, ormethoctramine, and the compounds disclosed in WO01/04118, the disclosureof which is hereby incorporated by reference.

Suitable antihistamines (also referred to as H₁-receptor antagonists)include any one or more of the numerous antagonists known which inhibitH₁-receptors, and are safe for human use. All are reversible,competitive inhibitors of the interaction of histamine withH₁-receptors. The majority of these inhibitors, mostly first generationantagonists, have a core structure, which can be represented by thefollowing formula:

This generalized structure represents three types of antihistaminesgenerally available: ethanolamines, ethylenediamines, and alkylamines.In addition, other first generation antihistamines include those whichcan be characterized as based on piperizine and phenothiazines. Secondgeneration antagonists, which are non-sedating, have a similarstructure-activity relationship in that they retain the core ethylenegroup (the alkylamines) or mimic the tertiary amine group withpiperizine or piperidine. Exemplary antagonists are as follows:

-   Ethanolamines: carbinoxamine maleate, clemastine fumarate,    diphenylhydramine hydrochloride, and dimenhydrinate.-   Ethylenediamines: pyrilamine amleate, tripelennamine HCl, and    tripelennamine citrate.-   Alkylamines: chiropheniramine and its salts such as the maleate    salt, and acrivastine.-   Piperazines: hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl,    cyclizine lactate, meclizine HCl, and cetirizine HCl.-   Piperidines: Astemizole, levocabastine HCl, loratadine or its    descarboethoxy analogue, and terfenadine and fexofenadine    hydrochloride or another pharmaceutically acceptable salt.-   Azelastine hydrochloride is yet another H₁ receptor antagonist which    may be used in combination with a PDE4 inhibitor.-   Examples of preferred anti-histamines include methapyrilene and    loratadine.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with aPDE4 inhibitor.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with acorticosteroid.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan anticholinergic.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan antihistamine.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with aPDE4 inhibitor and a corticosteroid.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan anticholinergic and a PDE-4 inhibitor.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with aphysiologically acceptable diluent or carrier represent a further aspectof the invention.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. Appropriate doses of known therapeutic agents will bereadily appreciated by those skilled in the art.

According to a further aspect of the invention, there is provided aprocess for preparing a compound of formula (I), (Ia) or (Ib) or a salt,solvate, or physiologically functional derivative thereof whichcomprises a process (a) (b) (c) or (d) as defined below followed by thefollowing steps in any order:

-   -   (i) optional removal of any protecting groups;    -   (ii) optional separation of an enantiomer from a mixture of        enantiomers;    -   (iii) optional conversion of the product to a corresponding        salt, solvate, or physiologically functional derivative thereof.

In one general process (a), a compound of formula (I), (Ia) or (Ib) maybe obtained by deprotection of a protected intermediate, for example offormula (II):

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, m, and n areas defined for the compound of formula (I), (Ia) or (Ib), R⁸, R⁹, andR¹⁰ are each independently either hydrogen or a protecting groupprovided that at least one of R⁸, R⁹, and R¹⁰ is a protecting group, andR¹⁴ is either hydrogen or a protecting group.

Suitable protecting groups may be any conventional protecting group suchas those described in “Protective Groups in Organic Synthesis” byTheodora W Greene and Peter G M Wuts, 3rd edition (John Wiley & Sons,1999). Examples of suitable hydroxyl protecting groups represented by R⁸and R⁹ are esters such as acetate ester, aralkyl groups such as benzyl,diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl. Examples ofsuitable amino protecting groups represented by R¹⁰ include benzyl,α-methylbenzyl, diphenylmethyl, triphenylmethyl, benzyloxycarbonyl,tert-butoxycarbonyl, and acyl groups such as trichloroacetyl ortrifluoroacetyl.

As will be appreciated by the person skilled in the art, use of suchprotecting groups may include orthogonal protection of groups in thecompounds of formula (II) to facilitate the selective removal of onegroup in the presence of another, thus enabling selectivefunctionalisation of a single amino or hydroxyl function. For example,the —CH(OH) group may be orthogonally protected as —CHOR¹⁴ using, forexample, a trialkylsilyl group such as triethylsilyl. A person skilledin the art will also appreciate other orthogonal protection strategies,available by conventional means as described in Theodora W Greene (seeabove).

The deprotection to yield a compound of formula (I), (Ia) or (Ib) may beeffected using conventional techniques. Thus, for example, when R⁸, R⁹,and/or R¹⁰ is an aralkyl group, this may be cleaved by hydrogenolysis inthe presence of a metal catalyst (e.g. palladium on charcoal).

When R⁸ and/or R⁹ is tetrahydropyranyl this may be cleaved by hydrolysisunder acidic conditions. Acyl groups represented by R¹⁰ may be removedby hydrolysis, for example with a base such as sodium hydroxide, or agroup such as trichloroethoxycarbonyl may be removed by reduction with,for example, zinc and acetic acid. Other deprotection methods may befound in Theodora W Greene (see above). In a particular embodiment ofprocess (a), R⁸ and R⁹ may together represent a protecting group as inthe compound of formula (III).

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R¹⁴, m, and nare as defined for the compound of formula (I), (Ia) or (Ib), R¹¹ andR¹² are independently selected from hydrogen, C₁₋₆alkyl, or aryl. In apreferred aspect, both R¹¹ and R¹² are methyl.

A compound of formula (III) may be converted to a compound of formula(I), (Ia) or (Ib) by hydrolysis with dilute aqueous acid, for exampleacetic acid or hydrochloric acid in a suitable solvent or bytransketalisation in an alcohol, for example ethanol, in the presence ofa catalyst such as an acid (for example, toluenesulphonic acid) or asalt (such as pyridinium tosylate) at normal or elevated temperature.

It will be appreciated that the protecting groups R⁸, R⁹, R¹⁰ and R¹⁴(including the cyclised protecting group formed by R⁸ and R⁹ as depictedin formula (III) may be removed in a single step or sequentially. Theprecise order in which protecting groups are removed will in part dependupon the nature of said groups and will be readily apparent to theskilled worker. Preferably, when R⁸ and R⁹ together form a protectinggroup as in formula (III) this protecting group is removed together withany protecting group on the CH(OH) moiety, followed by removal of R¹⁰.

Compounds of formulae (II) and (III) wherein R¹⁰ is hydrogen may beprepared from the corresponding compound of formula (IV):

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R⁸, R⁹ m, andn are as defined for the compound of formula (II) or (III).

The conversion of a compound of formula (IV) to a compound of formula(II) or (III) may be effected by treatment with a base, for example anon-aqueous base, such as potassium trimethylsilanoate, or an aqueousbase such as aqueous sodium hydroxide, in a suitable solvent such astetrahydrofuran.

Compounds of formula (IV) may be prepared from the correspondingcompound of formula (V):

or a salt or solvate thereof, wherein R⁴, R⁵, R⁸, R⁹, m and n are asdefined for the compound of formula (IV);by coupling with a compound of formula (VI):

wherein R¹, R², and R³ are as defined for the compound of formula (IV)and L is a leaving group, such as a halo group (typically, bromo oriodo) or a sulphonate ester such as a haloalkyl sulphonate (typically,trifluoromethanesulphonate), followed by reduction.

The coupling of compound of formula (V) with a compound of formula (VI)is conveniently effected in the presence of a catalyst system such asbis(triphenylphosphine)palladium dichloride with an organic base such asa trialkylamine, for example, triethylamine, in a suitable solvent, forexample acetonitrile or dimethylformamide. The resulting alkyne may thenbe reduced, either with or without being isolated to form the compoundof formula (IV). The reduction may be effected by any suitable methodsuch as hydrogenation in the presence of a catalyst, for example,palladium/charcoal or platinum oxide.

Alternatively, in the compounds of formula (VI) R¹, R², and R³ mayrepresent groups convertible into R¹, R², and R³, for example halogroups. This is particularly useful where one of the groups R¹, R², andR³ may be affected by any of the subsequent transformations. Thus, forexample, where R¹ contains an alkenylene moiety, this is preferablyintroduced after the reduction of the alkyne formed by reaction ofcompounds (V) and (VI).

Compounds of formula (VI) are commercially available or may be preparedby methods well known to the person skilled in the art.

Compounds of formula (V) may be prepared by coupling a compound offormula (VII):

or a salt or solvate thereof, wherein R⁸ and R⁹ are as defined for thecompound of formula (V) with a compound of formula (VIII):L¹CR⁴R⁵(CH₂)_(m)—O—(CH₂)_(n-2)—C≡CH  (VIII)wherein R⁴, R⁵, m and n are as defined for the compound of formula (V)and L¹ is a leaving group, for example a halo group (typically bromo oriodo) or a sulphonate such as an alkyl sulphonate (typically,methanesulphonate), an arylsulphonate (typically, toluenesulphonate), ora haloalkyl sulphonate (typically, trifluoromethanesulphonate).

The coupling of a compound of formula (VII) with a compound of formula(VIII) may be effected in the presence of a base, such as a metalhydride, for example sodium hydride, or an inorganic base such as cesiumcarbonate, in an aprotic solvent, for example dimethylformamide.

Compounds of formula (VIII) may be prepared from the correspondingdihaloalkane and hydroxyalkyne by conventional chemistry, typically inthe presence of an inorganic base, such as aqueous sodium hydroxide,under phase transfer conditions in the presence of a salt such astetraalkylammonium bromide.

Compounds of formula (VII) may be prepared by ring closure of a compoundof formula (IX):

wherein R⁸ and R⁹ are as defined for the compound of formula (VII) andR¹³ is C₁₋₆alkyl, for example tert-butyl, or aryl, for example phenyl.The ring closure may be effected by treatment with a base, such as ametal hydride, for example sodium hydride, in the presence of an aproticsolvent, for example, dimethylformamide.

Compounds of formula (IX) may be prepared from the corresponding ketoneof formula (X):

wherein R⁸ and R⁹ and R¹³ are as defined for the compound of formula(IX), by reduction by any suitable method, for example by treatment withborane, in the presence of a chiral catalyst, such asCBS-oxazaborolidine, in a suitable solvent such as tetrahydrofuran.

The compound of formula (X) may be prepared from the correspondinghalide of formula (XI)

wherein R⁸ and R⁹ are as defined for the compound of formula (X) and Yis halo, suitably bromo.

The conversion of a compound of formula (XI) to a compound of formula(X) may be effected by reaction with the protected amine HN(COOR¹³)₂wherein R¹³ is as defined for the compound of formula (X) in thepresence of an inorganic base such as cesium carbonate, followed byselective removal of one of the COOR¹³ groups, for example by treatmentwith an acid such as trifluoroacetic acid.

Compounds of formula (XI) may be prepared from the correspondingcompound having free hydroxymethyl and hydroxy substituents (whichitself may be prepared from2-bromo-1-(4-hydroxy)-3-hydroxymethyl-phenethyl)ethanone, thepreparation of which is described in GB2140800, by treatment with2-methoxypropane in acetone in the presence of an acid e.g.p-toluene-sulphonic acid in a nitrogen atmosphere or by other standardmethods) by forming the protected groups R⁸OCH₂— and R⁹O— wherein R⁸ andR⁹ are as defined for the compound of formula (XI). Such methods aredescribed in DE 3513885 (Glaxo).

Compounds of formula (II) or (III) wherein R¹⁰ is a protecting group maybe prepared as described in process (b) below, or by analogous methodsto process (c) below.

In a further process (b), a compound of formula (I), (Ia) or (Ib) may beobtained by alkylation of an amine of formula (XII):

wherein R⁸, R⁹, R¹⁰ and R¹⁴ are each independently either hydrogen or aprotecting group. Suitable protecting groups are discussed in thedefinition of compounds of formula (II);with a compound of formula (XIII):

wherein R¹, R², R³, R⁴, R⁵, m, and n are as defined for the compound offormula (I), (Ia) or (Ib) and L² is a leaving group such as halo(typically bromo); followed by removal of any protecting groups presentby conventional methods as described above for the deprotection ofcompounds of formula (II).

The reaction of compounds of formulae (XII) and (XIII) is optionallyeffected in the presence of an organic base such as a trialkylamine, forexample, diisopropylethylamine, and in a suitable solvent for exampledimethyl formamide.

Compounds of formula (XII) are known in the art (for example EP-A0947498) or may be readily prepared by a person skilled in the art.

Compounds of formula (XIII) may be prepared by coupling a compound offormula (VI) as defined above, or a precursor thereof (wherein one ormore of the substituents R¹, R² or R³ is a group which is convertible tothe desired group R¹, R², or R³) with a compound of formula (VIII) asshown above wherein R⁴, R⁵, m, and n are as defined for the compound offormula (XIII) and L¹ is a leaving group as defined above.

The coupling of a compound of formula (VIII) with a compound (VI) may beeffected by methods analogous to those described above for coupling acompound of formula (V) with a compound of formula (VI), followed byreduction of the resulting alkyne of formula (XIV):

also as described above. If necessary, the substituents R¹, R², and/orR³ may be formed by conventional conversions where a precursor ispresent.

An alkyne of formula (XIV) may also be prepared by reacting a compoundof formula (XV):L²CR⁴R⁵(CH₂)m L³  (XV)with a compound of formula (XVI):

using conventional methods, for example as described for the preparationof compounds (VIII).

Compounds of formula (XVI) may be prepared by reacting a hydroxyalkyne

with a compound of formula (VI) using methods analogous to thosedescribed above for coupling a compound (V) with a compound (VI).

In a further process (c) a compound of formula (I), (Ia) or (Ib) may beprepared by reacting a compound of formula (XVII):

wherein R⁸, R⁹ and R¹⁴ are as hereinbefore defined and L⁴ is a leavinggroup, is reacted with an amine of formula (XVIII):

followed by removal of any protecting groups present by conventionalmethods as described above for the deprotection of compounds of formula(II).

The reaction may be effected using conventional conditions for suchdisplacement reactions.

Compounds of formula (XVII) may be prepared by methods known in the art.

Compounds of formula (XVIII) may be prepared by reacting a compound offormula (XIII) with an amine R¹⁰NH₂.

In a further process (d) a compound of formula (I), (Ia) or (Ib) may beprepared by removal of a chiral auxiliary from a compound of formula(IIa):

wherein R¹-R⁵, R⁸, R⁹, m and n are as hereinbefore defined and R¹⁵represents a chiral auxiliary.

A “chiral auxiliary” is a moiety that is introduced into a molecule toinfluence the stereochemistry of the product formed, and is removed inwhole or part at a later time. A chiral auxiliary may simultaneouslyfunction as a protecting group.

Many chiral auxiliaries are commercially available, and persons skilledin the art would choose one based on the properties desired i.e. theabsolute stereochemistry desired and compatibility with the processesbeing used. Chiral auxiliaries suitable for use in this process includebut are not limited to the S-isomer and/or the R-isomer of phenylglycinol and substituted derivatives thereof.

The chiral auxiliary is preferably a moiety of the formula:

or a single enantiomer thereof, wherein R¹⁶ represents C₁₋₆alkyl oroptionally substituted phenyl or benzyl wherein the optionalsubstitution is one or more independently selected from C₁₋₆alkyl,halogen, hydroxy, C₁₋₆alkoxy or nitro e.g. para-hydroxyphenyl.

More preferably the chiral auxiliary is a moiety:

wherein R¹⁶ is as defined above. Alternatively it may be a moiety offormula:

wherein R¹⁶ is as defined above.

Preferably R¹⁶ represents phenyl optionally substituted as describedabove, Most preferably R represents unsubstituted phenyl.

The chiral auxiliary in this process may typically be removed byhydrogenolysis using for example a palladium on carbon catalyst orpreferably using palladium hydroxide (Pearlman's catalyst).Advantageously when Pearlman's catalyst is used the removal of thechiral auxiliary is most efficient. This method of removal is especiallysuitable where R¹ is phenyl or a substituted phenyl. Alternatively thenitrogen, to which the auxiliary is attached, may be derivatised underoxidising conditions to form the N-oxide before elimination by heatingto give a secondary amine.

A compound of formula (IIa) may be prepared by reduction of thecorresponding alkyne of formula (XIX):

Preferably in the compounds of formulae (IIa) and (XIX) the protectinggroups R⁸ and R⁹ together form a group —CR¹¹R¹²— as in the compounds offormula (III).

Reduction of an alkyne of formula (XIX) may be effected by methods wellknown in the art, for example by catalytic hydrogenation, usingpalladium on charcoal or more preferably palladium hydroxide (Pearlman'scatalyst). The chiral auxiliary may also be removed under reductiveconditions. Advantageously, therefore the reduction of the alkyne andremoval of the chiral auxiliary may be effected concomitantly in a‘one-pot’ reaction.

An alkyne of formula (XIX) may be prepared by reaction of a compound offormula (XX)

with a compound of formula (VI) under conditions described above forcoupling of compounds (V) and (VI).

A compound of formula (XX) may be prepared by reacting a compound offormula (XIIa):

with an aldehyde of formula (XXI):

using known methods for effecting reductive amination, e.g. sodiumtriacetoxyborohydride in a solvent such as chloroform

An aldehyde of formula (XXI) may be prepared from a corresponding halideof formula (VIII) using standard techniques such as treatment withsodium bicarbonate in a solvent such as DMSO at elevated temperature,preferably in the range 130-160° C.

A compound of formula (XIIa) may be prepared from a compound of formula(XXII):

Wherein R⁸, R⁹ and R¹⁵ are as hereinbefore defined by treatment with areducing agent such as a hydride source e.g. sodium borohydride.Preferably this process takes place in the presence of an inert metalsalt such as calcium chloride suitably at non-extreme temperatures e.g.below ambient, such as 0° C. This allows the desired stereochemistry tobe introduced efficiently with good enantiomeric excess at an earlystage in the synthesis, using inexpensive and relatively harmlessreagents. Furthermore, the enantiomeric excess may be increased byrecrystallisation of the product of this process.

A compound of formula (XXII) may be prepared from a compound of formula(XI) as hereinbefore defined by reaction with an appropriate chiralamine, e.g. (S)-phenylglycinol, in the presence of a non-nucleophilicbase in an inert solvent at non-extreme temperatures.

A detailed description of a process analogous to Route (d) may be foundin published International Application Number WO/0196278.

In the above process (d) it is preferred that the protecting groups R⁸and R⁹ together form a protecting group as depicted in formula (III).

It will be appreciated that in any of the routes (a) to (d) describedabove, the precise order of the synthetic steps by which the variousgroups and moieties are introduced into the molecule may be varied. Itwill be within the skill of the practitioner in the art to ensure thatgroups or moieties introduced at one stage of the process will not beaffected by subsequent transformations and reactions, and to select theorder of synthetic steps accordingly.

The enantiomeric compounds of the invention may be obtained (i) byseparation of the components of the corresponding racemic mixture, forexample, by means of a chiral chromatography column, enzymic resolutionmethods, or preparing and separating suitable diastereoisomers, or (ii)by direct synthesis from the appropriate chiral intermediates by themethods described above.

Optional conversions of a compound of formula (I), (Ia) or (Ib) to acorresponding salt may conveniently be effected by reaction with theappropriate acid or base. Optional conversion of a compound of formula(I), (Ia) or (Ib) to a corresponding solvate or physiologicallyfunctional derivative may be effected by methods known to those skilledin the art.

According to a further aspect, the present invention provides novelintermediates for the preparation of compounds of formula (I), (Ia) or(Ib), for example:

compounds of formula (II) and (III) as defined above, or an opticalisomer, a salt, or a protected derivative thereof; particularly, acompound selected from:

-   3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;-   4-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;-   2-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;-   3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-N-methylbenzenesulfonamide;-   (1R)    1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-(morpholin-4-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol;-   3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-N,N-dimethylbenzenesulfonamide;-   3-{4-[(6-{[(2R)-2-2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-N-isopropylbenzenesulfonamide;-   N-(tert-Butyl)-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;    and-   (1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-piperidin-1-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol;-   (1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-(piperazin-1-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol;-   3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-amino}hexyl)oxy]butyl}-N-(1-methyl-1-phenylethyl)benzenesulfonamide;-   N-[4-(Aminosulfonyl)phenyl]-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;-   {3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4-H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-amino}hexyl)oxy]butyl}phenyl}methanesulfonamide;-   5-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-2-methoxybenzenesulfonamide;-   3-{5-[(5-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-amino}pentyl)oxy]pentyl}benzenesulfonamide;-   3-{3-[(7-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-amino}heptyl)oxy]propyl}benzenesulfonamide;-   3-[6-(4-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-amino}butoxy)hexyl]benzenesulfonamide;-   3-{3-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]propyl}benzenesulfonamide;-   3-{4-[(5-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}pentyl)oxy]butyl}benzenesulfonamide;-   N-[3-(Aminosulfonyl)phenyl]-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;-   N-Benzyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;-   3-{4-[(6-{[2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;-   3-{4-[(6-{[(2S)-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;-   N-(4-{[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]amino}phenyl)acetamide;-   N-Cyclobutyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;-   N-Cyclohexyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide;-   3-{4-[(6-{[(2R-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-N-(4-fluorophenyl)benzenesulfonamide;-   3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}-hexyl)oxy]butyl}-N-(2-morpholin-4-ylethyl)benzenesulfonamide;-   (E)-2-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-N-methylethenesulfonamide;-   (E)-2-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)ethenesulfonamide;-   5-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}[1,1′-biphenyl]-3-sulfonamide;-   3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-5-pentylbenzenesulfonamide;    compounds of formula (IV) as defined above, or an optical isomer, a    salt, or a protected derivative thereof; particularly, a compound    selected from:-   3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;-   N-[4-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;-   3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-4-fluorophenyl)benzenesulfonamide;-   3-[4-{6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-(2-morpholin-4-ylethyl)benzenesulfonamide;-   N-Cyclohexyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;-   4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;-   2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;-   (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(piperazin-1-ylsulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one;-   3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-(1-methyl-1-phenylethyl)benzenesulfonamide;-   3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-methylbenzenesulfonamide;-   (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(morpholin-4-ylsulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one;-   3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N,N-dimethylbenzenesulfonamide;-   3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-isopropylbenzenesulfonamide;-   N-(tert-Butyl)-3-[4-({6-[(5R-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;-   (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(piperidin-1-ylsulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one;-   3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenylmethanesulfonamide;-   3-[5-({5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]pentyl}oxy)pentyl]benzenesulfonamide;-   5-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-2-methoxybenzenesulfonamide;-   3-[3-({7-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]heptyl}oxy)propyl]benzenesulfonamide;-   3-(6-{4-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]butoxy}hexyl)benzenesulfonamide;-   4-{3-[4-({6-[(5R)-5-2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}butane-1-sulfonamide;-   3-[5-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)pentyl]benzenesulfonamide;-   3-[6-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)hexyl]benzenesulfonamide;-   3-[3-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)propyl]benzenesulfonamide;-   3-[4-({5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]pentyl}oxy)butyl]benzenesulfonamide;-   N-[3-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;-   N-Benzyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;-   3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-[(ethylamino)carbonyl]benzenesulfonamide;-   3-[4-({6-[5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;-   N-{4-[({3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}sulfonyl)amino]phenyl}acetamide;-   N-Cyclobutyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide;-   3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-[2-(2-hydroxyethoxy)ethyl]benzenesulfonamide;-   (E)-2-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}-N-methylethenesulfonamide;-   (E)-2-{3-[4-({6-[(5R)-5-2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}ethenesulfonamide;-   3-[((tert-Butoxycarbonyl){[2-(trimethylsilyl)ethoxy]methyl}amino)sulfonyl]-5-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-1,1′-biphenyl;-   tert-Butyl    {3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-5-pentylphenyl}sulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate;-   1-{4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}methanesulfonamide;    and-   1-{2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}methanesulfonamide.

For a better understanding of the invention, the following Examples aregiven by way of illustration.

SYNTHETIC EXAMPLES

Throughout the examples, the following abbreviations are used:

-   LC: Liquid Chromatography-   LCMS: Liquid Chromatography Mass Spectrometry.-   RT: retention time-   THF: tetrahydofuran-   DMF: N,N-dimethylformamide-   bp: boiling point-   ca: circa-   h: hour(s)-   min: minute(s)-   XRPD: X-ray powder diffraction-   All temperatures are given in degrees centigrade.-   Silica gel refers to Merck silica gel 60 Art number 7734.-   Flash silica gel refers to Merck silica gel 60 Art number 9385.-   Biotage refers to prepacked silica gel cartridges containing KP-Sil    run on flash 12i chromatography module.-   Bond Elut are prepacked cartridges used in parallel purifications,    normally under vacuum. These are commercially available from Varian.

LC was conducted on a Luna C18(2) column (5 cm×2.0 mm ID) eluting with0.05% v/v trifluoroacetic acid in water (solvent A) and 0.05% v/vtrifluoroacetic acid in acetonitrile (solvent B) using the followingelution gradient 0.00-8.00 min 0% B, 8.00-8.01 min 95% B, 8.01-10.00 min0% B at a flow rate of 1.0 mL/min with a column temperature of 40° C.

NMR experiments at 400 MHz (unless specified otherwise).

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6 mm ID)eluting with 0.1% HCO₂H and 0.01 M ammonium acetate in water (solventA), and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using thefollowing elution gradient 0-0.7 min 0% B, 0.7-4.2 min 100% B, 4.2-5.3min 0% B, 5.3-5.5 min 0% B at a flow rate of 3 ml/min. The mass spectrawere recorded on a Fisons VG Platform spectrometer using electrospraypositive and negative mode (ES+ve and ES−ve).

The XRPD analysis shown in the Figures were performed on a PhillipsX'pert Pro powder diffractometer, Model PW3040/60, serial number DY1379.The method runs from 2 to 45 degrees 2Theta with 0.02 degree 2Theta stepsize and a 2 second collection time at each step.

Example 13-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-hexyl]oxy}butyl)benzenesulfonamideacetate i)Di(tert-butyl)2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate

Cesium carbonate (70.4 g) was added to a stirred suspension of2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone, (Glaxo, DE3513885, 1985) (61.8 g) and di-t-butyl iminodicarboxylate (47.15 g) inacetonitrile (600 ml) under nitrogen. After vigorous stirring at 21° for24 h the mixture was diluted with water (ca800 ml) and the product wasextracted with diethyl ether (1 liter, then 200 ml). The combinedorganic layers were washed with brine, dried (MgSO₄) and concentrated toca400 ml. The white crystals were collected by filtration, washed withdiethyl ether and dried to give the title compound (24.4 g) δ (CDCl₃)7.78(1H, dd, J 8, 2 Hz), 7.65 (1H, brs), 6.87(1H, d, J 8 Hz), 4.97(2H,s), 4.88(2H, s), 1.56(6H, s) and 1.48 (18H, s). Further concentration ofthe mother liquors gave additional product (13.8 g). A third crop (7.1g) was obtained by chromatographing the mother liquors on silica gel,evaporating the appropriate eluate and triturating with diethyl ether.

ii) tert-Butyl2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate

Trifluoroacetic acid (92 ml) was added to a stirred solution ofdi(tert-butyl)2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate,(352.55 g) in dichloromethane (3.6 liters) at 21° and the reaction wasstirred for 1.5 h. Aqueous NaOH solution (1.75 liters) was added andafter 10 min the phases were separated. The organic layer was washedwith water, dried (MgSO₄) and evaporated to an oil. This was storedunder high vacuum overnight and then triturated with hexane:ether (3:1)to give the crude product (226.61 g). This was purified byrecrystallisation from diethyl ether to give the title compound (122.78g). Further product (61.5 g) was obtained from the mother liquors byevaporation and chromatography on a Biotage using 15% ethyl acetate inhexane. LCMS RT=3.37 min.

iii)tert-Butyl(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate

A 2M solution of borane-dimethyl sulphide in THF (28 ml) was addedslowly to a 1M solution of(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborolein toluene (56 ml) at 0° under nitrogen. A solution of tert-butyl2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate, (108.2 g)in THF (1.3 liters) was added slowly keeping the temperature below 5°followed by 2M solution of borane-dimethyl sulphide in THF (252 ml) over50 min. After 1 h, 2M HCl (170 ml) was added with cooling and themixture was partitioned between ethyl acetate and water. The organiclayer was washed with saturated NaHCO₃ solution and brine and dried(MgSO₄). The solution was concentrated and the product purified bychromatography on flash silica gel (800 g), eluting successively withhexane:ethyl acetate (4:1 then 3:1) to give the title compound (93.3 g),LCMS RT=3.31 min.

iv) (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

tert-Butyl(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate,(86.37 g) in DMF (600 ml) was added dropwise to a stirred suspension ofsodium hydride (60% oil dispersion, 11.9 g) in DMF (160 ml) with coolingsuch that the internal temperature remained at 0° under nitrogen. Themixture was stirred at 21° for 2 h. The mixture was recooled to 0° and2M HCl (134 ml) was added. The mixture was diluted with water and theproduct was extracted with ethyl acetate twice. The solution was washedwith brine twice, dried (MgSO₄) and evaporated to give the titlecompound (63.55 g) LCMS RT=2.66 min.

v) 6-Bromohexyl but-3-ynyl ether

3-Butyn-1-ol (42.4 ml) was stirred vigorously with 1,6-dibromohexane(260 ml) and tetrabutylammonium bisulphate (2.4 g) in 50% aqueous sodiumhydroxide solution (200 ml) under nitrogen for 3 days. Water (ca 700 ml)was added and the organic layer was separated. The aqueous layer wasextracted twice with dichloromethane (2×100 ml) and the combined organiclayers were washed with water, dried (MgSO₄) and concentrated. Theresidue in petroleum ether (bp 40-60°) was loaded onto a column ofsilica gel (1.5 kg) and the column was eluted with petroleum ether (bp40-60°), then 10% diethyl ether in petroleum ether (bp 40-60°) to givethe title compound (103.3 g), δ (CDCl₃) 3.56(2H, t, J 7 Hz), 3.47(2H, t,J 7 Hz), 3.42(2H, t, J 7 Hz), 2.45(2H, m), 1.99(1H, t, J 2 Hz), 1.87(2H,m), 1.60(2H, m) and 1.50 to 1.33 (4H, m).

vi)(5R)-3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (10g) in DMF (100 ml) was added dropwise to a stirred suspension of sodiumhydride (60% oil dispersion, 2.33 g) in DMF (50 ml) with stirring undernitrogen and maintaining the internal temperature at 0°. Stirring wascontinued at 0-5° for 1 h. The mixture was recooled to 0° and a solutionof 6-bromohexyl but-3-ynyl ether (14.7 g) in DMF (50 ml) was added over1 min. The mixture was then stirred at 20-30° for 2 h. 2M HCl (9 ml) wasadded and the mixture was partitioned between water and diethyl ether.The aqueous layer was extracted with more diethyl ether and the combinedorganic layers were washed twice with brine. After drying (MgSO₄) thesolution was concentrated and loaded onto a column of silica gel (600 g)set up in diethyl ether:petroleum ether (bp 40-60°) (1:2). The columnwas eluted successively with this mixture, then (1:1) and then diethylether to give the title compound (13.88 g) LCMS RT=3.45 min.

vii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide

(5R)-3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(1.79 g) was stirred with 3-iodobenzene sulphonamide (1.4 g) inacetonitrile:triethylamine (1:1, 42 ml) under nitrogen for 10 min.Cuprous iodide (0.083 g) and dichlorobis(triphenylphosphine)palladium(0.192 g) were added and the mixture was stirred for 17 h under nitrogenat 21°. The mixture was evaporated to dryness and the residue waschromatographed on silica gel (250 g) in 30% ethyl acetate:petroleumether (bp 40-60°), then 50%, then 75% and finally ethyl acetate to givethe title compound (2.35 g), LCMS RT=3.44 min.

viii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide(2.35 g) was stirred with platinum oxide (0.3 g) in THF (30 ml) underhydrogen for 2 h. The catalyst was removed by filtration using a filteraid and the filter cake was leached with ethyl acetate. The combinedfiltrates were passed through silica gel (200 g) in ethyl acetate andthe eluate was evaporated to give the title compound (2.32 g), LCMSRT=3.49 min.

ix)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide(0.43 g) was stirred in THF (10 ml) while purging with a vigorous streamof nitrogen for 5 min. Potassium trimethylsilanoate (0.43 g) was addedand the mixture was stirred at 70° under nitrogen for 2.5 h. The mixturewas partitioned between dichloromethane and pH 6.4 phosphate buffer andthe aqueous layer was extracted with more dichloromethane. The combinedorganic layers were washed with water, dried (MgSO₄) and concentrated.The residue was purified on silica gel (60 g), eluting successively withethyl acetate:petroleum ether (bp 40-60°) (1:1), ethyl acetate, 10% then20% methanol in ethyl acetate to give the title compound (0.286 g), LCMSRT=2.56 min.

x)3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide(0.283 g) was stirred with acetic acid (8 ml) and water (4 ml) at 70°for 35 min before evaporating to dryness. The residue was re-evaporatedtwice with toluene to give the title compound (0.318 g) LCMS RT=2.34min, ES+ve 495 (MH)⁺. Example 24-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate i)4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.47 min.

ii)4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.47 min.

iii)4-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.65 min.

iv)4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.38 min, ES+ve 495 (MH)⁺.

Example 32-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate i)2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.58 min.

ii)2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.61 min.

iii)2-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.80 min.

iv)2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.43 min, ES+ve 495 (MH)⁺.

Example 43-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N-methylbenzenesulfonamideacetate i)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-N-methylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.

ES+ve 571 (MH)⁺.

ii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-methylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 575 (MH)⁺.

iii)3-{4-[(6-{[(2R-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-N-methylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 549 (MH)⁺.

iv)3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N-methylbenzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.

LCMS RT=2.45 min ES+ve 509 (MH)⁺.

Example 52-Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(morpholin-4-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethyl}phenolacetate i)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-({4-[3-(morpholin-4-ylsulfonyl)phenyl]but-3-ynyl}oxy)hexyl]-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 vii.ES+ve 627 (MH)⁺.

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(morpholin-4-ylsulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 viii.ES+ve 631 (MH)⁺.

iii)(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-(morpholin-4-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol

was prepared using methods similar to those described in Example 1 ix.

ES+ve 605 (MH)⁺.

iv)2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(morpholin-4-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethyl}phenolacetate

was prepared using methods similar to those described in Example 1x.LCMS RT=2.54 min ES+ve 565 (MH)⁺.

Example 63-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N,N-dimethylbenzenesulfonamideacetate i)3-[4-({6-[(5R)-5-2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-N,N-dimethylbenzenesulfonamide

A mixture of(5R)-3-[6-(but-3-ynyloxy)hexyl]-5-2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(0.256 g) and 3-bromo-N,N-dimethylbenzene sulphonamide (0.208 g) inpyrrolidine (4 ml) was degassed using vacuum/nitrogen cycle. Cuprousiodide (0.005 g) and dichlorobis(triphenylphosphine)palladium (0.037 g)were added and the mixture was stirred at 80° for 45 min under nitrogen.The mixture was diluted with EtOAc and washed with water. The aqueousphase was extracted with EtOAc and the combined organic phases washedwith brine, dried (Na₂SO₄) and evaporated to dryness. The residue wasdissolved in CH₂Cl₂ and applied to a silica Bond Elut Cartridge (10 g).The cartridge was eluted with CH₂Cl₂, cyclohexane/Et₂O, Et₂O and EtOAc.Evaporation of the ether fractions gave an oil which was repurified bysilica Bond Elut to give the title compound (0.23 g), ES+ve 585 (MH)⁺.

ii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N,N-dimethylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 587 (MH)⁺.

iii)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-N,N-dimethylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 563 (MH)⁺.

iv)3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N,N-dimethylbenzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.52 min ES+ve 523 (MH)⁺.

Example 73-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N-isopropylbenzenesulfonamideacetate i)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-N-isopropylbenzenesulfonamide

was prepared using methods similar to those described in Example 6 i.ES+ve 599 (MH)⁺.

ii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-isopropylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 603 (MH)⁺.

iii)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-N-isopropylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 577 (MH)⁺.

iv)3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N-isopropylbenzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.56 min ES+ve 537 (MH)⁺.

Example 8N-(tert-Butyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butylbenzenesulfonamideacetate i)N-(tert-Butyl)-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 6i.ES+ve 613 (MH)⁺.

ii)N-(tert-Butyl)-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 617 (MH)⁺.

iii)N-(tert-Butyl)-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 591 (MH)⁺.

iv)N-(tert-Butyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1x.LCMS RT=2.63 min ES+ve 551 (MH)⁺.

Example 92-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(piperidin-1-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethyl}phenolacetate i)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-({4-[3-(piperidin-1-ylsulfonyl)phenyl]but-3-ynyl}oxy)hexyl]-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 6 i.ES+ve 625 (MH)⁺.

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(piperidin-1-ylsulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 viii.ES+ve 629 (MH)⁺.

iii)(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-(piperidin-1-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol

was prepared using methods similar to those described in Example 1 ix.ES+ve 603 (MH)+.

iv)2-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-piperidin-1-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethyl}phenolacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.72 min ES+ve 563 (MH)⁺.

Example 101-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-hexyl]oxy}butyl)phenyl]methanesulfonamidei) Sodium(3-iodophenyl)methanesulfonate

A solution of 3-iodobenzyl bromide (3 g) and sodium sulphite (1.26 g) inacetone (15 ml) and water (30 ml) was heated at 70° for 3 h. The solventwas removed under reduced pressure and the residue was triturated inether to give the title compound (3.8 g). LCMS RT=3.66 min.

ii) (3-Iodophenyl)methanesulfonyl chloride

A stirred mixture of sodium (3-iodophenyl)methanesulfonate (3.6 g) andphosphoryl chloride (10 ml) in sulpholane (20 ml) and acetonitrile (30ml) was heated at 70° for 2 h. The mixture was-poured onto crushed ice(200 ml) and the precipitated product was collected and dried to givethe title product (2.8 g) LCMS RT=3.47 min.

iii) (3-Iodophenyl)methanesulfonamide

A stirred solution of (3-iodophenyl)methanesulfonyl chloride (1 g) inTHF (20 ml) was treated with 0.88 ammonia (25 ml) at room temperaturefor 30 min. The solvent was removed under reduced pressure and theresidue was triturated in ether to give the title compound (0.35 g).LCMS RT=2.71 min.

iv){3-[4-({6-[(5R)-5-2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin3-yl]hexyl}oxy)but-1-ynyl]phenyl}methanesulfonamide

was prepared using methods similar to those described in Example 1 vii.ES+ve 571 (MH)⁺

v)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenylmethanesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 575 (MH)⁺

vi){3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4-H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl}methanesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 549 (MH)⁺

vii)[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]-ethyl}amino)hexyl]oxy}butyl)phenyl]methanesulfonamide

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.22 min ES+ve 509 (MH)⁺

Example 113-(5-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}pentyl)benzenesulfonamideacetate i) 5-[(5-Bromopentyl)oxy]pent-1-yne

was prepared using methods similar to those described in Example 1 v.LCMS RT=3.62 min.

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[5-pent-4-ynyloxy)pentyl]-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 vi.LCMS RT=3.50 min.

iii)3-[5-({5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]pentyl}oxy)pent-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.42 min.

iv)3-[5-({5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]pentyl}oxy)pentyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.58 min.

v)3-{5-[(5-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}pentyl)oxy]pentyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.75 min.

vi)3-(5-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}pentyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.46 min, ES+ve 495 (MH)⁺.

Example 123-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamideacetate i) 3-[(7-Bromoheptyl)oxy]prop-1-yne

was prepared using methods similar to those described in Example 1 v.LCMS RT=3.63 min.

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[7-(prop-2-ynyloxy)heptyl]-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 vi.LCMS RT=3.57 min.

iii)3-[3-({7-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]heptyl}oxy)prop-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.5 min.

iv)3-[3-({7-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]heptyl}oxy)propyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.58 min.

v)3-{3-[(7-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.75 min.

vi)3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.46 min, ES+ve 495 (MH)⁺.

Example 133-{6-[4-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)butoxy]hexyl}benzenesulfonamideacetate i) 6-(4-Bromobutoxy)hex-1-yne

was prepared using methods similar to those described in Example 1 v.LCMS RT=3.49 min.

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[4-(hex-5-ynyloxy)butyl]-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 vi.LCMS RT=3.48 min.

iii)3-(6-{4-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]butoxy}hex-1-ynyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.42 min.

iv)3-(6-{4-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]butoxy}hexyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.58 min.

v)3-[6-(4-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}butoxy)hexyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.66 min.

vi)3-{6-[4-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)butoxy]hexyl}benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.47 min, ES+ve 495 (MH)⁺.

Example 144-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]butane-1-sulfonamidei) 4-(3-Iodophenyl)butyl methanesulfonate

4-(3-Iodophenyl)butan-1-ol (1.7 g) was stirred with diisopropylamine(1.74 ml) and methanesulfonyl chloride (0.66 ml) in dichloromethane (50ml) at 21° for 2 h. The solution was washed successively with sodiumbicarbonate solution, water, water acidified with a few drops of 2M HCland water, each time back extracting with dichloromethane. The combinedorganic layers were dried (MgSO₄) and evaporated to give the titlecompound (2.23 g), tlc R_(f)=0.28 (1:3 ethyl acetate in cyclohexane)

ii) 4-(3-Iodophenylbutane-1-sulfonamide

4-(3-Iodophenyl)butyl methanesulfonate (0.354 g) was stirred with sodiumiodide (0.75 g) in acetone (5 ml) under nitrogen for 3 h and at 35° for30 min. The mixture was partitioned between dichloromethane and water.The aqueous layer was extracted with more dichloromethane and thecombined organic layers were washed with water. After drying (MgSO₄) thesolution was evaporated to an oil. This was dissolved in ethanol (10 ml)and water (5 ml) and the mixture was refluxed on a steam bath for 12 hwith sodium sulfite (0.138 g). The mixture was cooled and the solid wascollected by filtration, washed with water and dried. This residue wasrefluxed with phosphorus oxychloride (4 ml) under nitrogen for 4 h andthen blown dry with a stream of nitrogen. 0.880 Ammonia solution (5 ml)was added and the mixture was refluxed for 2 h. More ammonia solution (5ml) was added and refluxing was continued for 45 min. The mixture wascooled and the solid was collected by filtration, washed with water anddried to give the title compound (0.2 g) LCMS RT=3.15 min.

iii)4-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}butane-1-sulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.62 min.

iv)4-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}butane-1-sulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.71 min.

v)4-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]butane-1-sulfonamide

4-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}butane-1-sulfonamide(0.097 g) was stirred and refluxed with potassium trimethylsilanoate(0.1 g) under nitrogen for 2 h. The mixture was evaporated to drynessand re-evaporated with methanol. The residue was taken up in methanoland loaded onto a Bond Elut SCX2 cartridge (10 g) which had beenpreconditioned with methanol. The cartridge was left for 30 min and theneluted successively with methanol and then 1% 0.880 aqueous ammoniasolution in methanol. This gave the title compound (0.064 g), LCMSRT=2.72 min, ES+ve 551 (MH)⁺.

Example 153-(5-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}pentyl)benzenesulfonamidei) 5-[(6-bromohexyloxy]pent-1-yne

was prepared using methods similar to those described in Example 1 v.GCMS RT=5.6 min

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(pent-4-ynyloxy)hexyl]-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 iv.LCMS RT=3.65 min

iii)3-[5-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)pent-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.76 min

iv)3-[5-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)pentyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.57 min

v)3-(5-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}pentyl)benzenesulfonamide

was prepared using methods similar to those described in Example 14 v.LCMS R=2.47 min, ES+ve 509 (MH)⁺.

Example 163-(6-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}hexyl)benzenesulfonamidei) 6-[(6-Bromohexyl)oxy]hex-1-yne

was prepared using methods similar to those described in Example 1 v.GCMS RT=5.99 min

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(hex-5-ynyloxy)hexyl]-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 iv.LCMS RT=3.73 min

iii)3-[6-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)hex-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.74 min

iv)3-[6-({6-[(5R)-5-(2,2-Dimethyl-4R-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)hexyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.69 min

v)3-(6-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}hexyl)benzenesulfonamide

was prepared using methods similar to those described in Example 14 v.LCMS RT=2.57 min, ES+ve 523 (MH)⁺.

Example 173-(3-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}propyl)benzenesulfonamideacetate i) 3-[(6-Bromohexyl)oxy]prop-1-yne

was prepared using methods similar to those described in Example 1 v. δ(CDCl₃) 4.13 (2H, s), 3.52 (2H, t, J 7 Hz), 3.41 (2H, t, J 7 Hz), 2.42(1H, t J 2 Hz), 1.91 to 1.82 (2H, m), 1.66 to 1.58 (2H, m) and 1.51 to1.35 (4H, m).

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(prop-2-ynyloxy)hexyl]-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 vi.LCMS RT=3.45 min

iii)3-[3-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)prop-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.52 min

iv)3-[3-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)propyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.48 min

v)3-{3-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]propyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.81 min

vi)3-(3-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}propyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.48 min, ES+ve 481 (MH)⁺.

Example 183-(4-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}butyl)benzenesulfonamideacetate i) 4-[(5-Bromopentyl)oxy]but-1-yne

was prepared using methods similar to those described in Example 1 v. δ(MeOD) 3.43 (2H, t, J 7 Hz), 3.41 to 3.32 (4H, m), 2.32 (2H, dt, J 2.7Hz), 2.15 (1H, t, J 2 Hz), 1.81 to 1.73 (2H, m), 1.54 to 1.38 (4H, m).

ii)(5R)-3-[5-(But-3-ynyloxy)pentyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 vi.LCMS RT=3.87 min

iii)3-[4-({5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]pentyl}oxy)but-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.47 min

iv)3-[4-({5-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]pentyl}oxy)butyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.37 min

v)3-{4-[(5-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}pentyl)oxy]butyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.81 min

vi)3-(4-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}butyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.41 min, ES+ve 481 (MH)⁺.

Example 19N-[3-Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetateN-[3-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.72 min.

i)N-[3-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.61 min.

ii)N-[3-(Aminosulfonyl)phenyl]-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.88 min.

iii)N-[3-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.95 min, ES+ve 650 (MH)⁺.

Example 201-[4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]methanesulfonamidei) Sodium (4-iodophenyl)methanesulfonate

was prepared using methods similar to those described in Example 10 i.tlc (SiO₂, 1:1 EtOAc/Cyclohexane/1% AcOH) Rf=0.57).

ii) 1-(4-Iodophenyl)methanesulfonamide

was prepared using methods similar to those described in Example 10 iii.LCMS RT=2.63 min

iii)1-{4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}methanesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.43 min

iv)1-{4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}methanesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.50 min

v)1-[4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]methanesulfonamide

was prepared using methods similar to those described in Example 14 v.LCMS RT=2.35, ES+ve 509 (MH)⁺.

Example 211-[2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]methanesulfonamidei) Sodium (2-iodophenyl)methanesulfonate

was prepared using methods similar to those described in Example 10 i.tlc (SiO₂, 1:1 EtOAc/Cyclohexane/1% AcOH) Rf=0.63.

ii) 1-(2-Iodophenyl)methanesulfonamide

was prepared using methods similar to those described in Example 10 iii.LCMS RT=2.44 min

iii)1-{2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}methanesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.46 min

iv)1-{2-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}methanesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.50 min

v)1-[2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]methanesulfonamide

was prepared using methods similar to those described in Example 14 v.LCMS RT=2.40, ES+ve 509 (MH)⁺.

Example 22N-Benzyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate i)N-Benzyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 6 i.ES+ve 647 (MH)⁺

ii)N-Benzyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 651 (MH)⁺

iii)N-Benzyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 625 (MH)⁺

iv) N-benzyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.72 min, ES+ve 585 (MH)⁺

Example 234-{(1R)-2-[(6-{4-[3-({[(Ethylamino)carbonyl]amino}sulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-1-hydroxy-2-(hydroxymethyl)benzeneacetate i)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-[(ethylamino)carbonyl]benzenesulfonamide

Ethyl isocyanate (0.015 g) was added to a stirred mixture of3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide(0.11 g) and K₂CO₃ (0.055 g) in acetone (2 ml). The mixture was heatedat reflux for 2 h then ethyl isocyanate (0.005 g) was added. After 0.5 hthe reaction mixture was cooled and quenched with water (1 ml). Themixture was partitioned between EtOAc (20 ml) and H₂O (20 ml). Theaqueous phase was extracted with EtOAc (20 ml). The combined EtOAcphases were washed with brine (10 ml) then dried (Na₂SO₄) andconcentrated. The residue was purified by SPE (silica 5 g) with CH₂Cl₂(2×15 ml), Et₂O (2×15 ml) and EtOAc (2×15 ml), evaporation of the EtOAcfractions afforded the title compound (0.067 g). ES+ve 632 (MH)⁺

ii)4-{(1R)-2-[(6-{4-[3-({[(Ethylamino)carbonyl]amino}sulfonyl)phenyl]butoxy}hexyl)amino]-1-hydroxyethyl}-1-hydroxy-2-(hydroxymethyl)benzeneacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.86 min, ES+ve 606 (MH)⁺

Example 243-(4-{[6-({2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate i) tert-Butyl2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate

Recrystallisation of a batch of 3:1 (R:S) Example 1 iii (78.94 g) gavethe title compound (27.6 g). LCMS RT=3.31 min

ii) 5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 iv.ES+ve 250 (MH)⁺

iii)3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 vi.ES+ve 402 (MH)⁺

iv)3-[4-({6-[5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.ES+ve 557 (MH)⁺

v)3-[4-({6-[5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 561 (MH)⁺

vi)3-{4-[(6-{[2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 535 (MH)⁺

vii)3-(4-{[6-({2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.90 min, ES+ve 495 (MH)⁺

Example 253-(4-{[6-({(2S-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate i)3-{4-[(6-{[(2S)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

Resolution of3-{4-[(6-{[2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide(0.403 g) on an HPLC Chiralcel OJ column using 40% ethanol/heptaneafforded the title compound (0.096 g).

ii)3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.44 min, ES+ve 495 (MH)⁺

Example 26N-[4-({[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}amino)phenyl]acetamideacetate i)N-{4-[({3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}sulfonyl)amino]phenyl}acetamide

was prepared using methods similar to those described in Example 1 vii.ES−ve 688 (M-H)⁻

ii)N-{4-[({3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}sulfonyl)amino]phenyl}acetamide

was prepared using methods similar to those described in Example 1 viii.ES−ve 692 (M-H)⁻

iii)N-(4-{[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]amino}phenyl)acetamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 668 (MH)⁺

iv)N-[4-({[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}amino)phenyl]acetamideacetate GW671337A R5965/48/11

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.59 min, ES+ve 628 (MH)⁺

Example 27N-Cyclobutyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate (i)N-Cyclobutyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.ES+ve 611 (MH)⁺

ii)N-Cyclobutyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 615 (MH)⁺

iii)N-Cyclobutyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 589 (MH)⁺

iv)N-Cyclobutyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.72 min, ES+ve 549 (MH)⁺

Example 28N-Cyclohexyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate i)N-Cyclohexyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.ES+ve 639 (MH)⁺

ii)N-Cyclohexyl-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 643 (MH)⁺

iii)N-Cyclohexyl-3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 617 (MH)⁺

iv)N-Cyclohexyl-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butylbenzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.85 min, ES+ve 577 (MH)⁺

Example 293-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-N-(2-morpholin-4-ylethyl)benzenesulfonamideacetate i)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-N-(2-morpholin-4-ylethyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.ES+ve 670 (MH)⁺

ii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-(2-morpholin-4ylethyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 674 (MH)⁺

iii)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-amino}hexyl)oxy]butyl}-N-(2-morpholin-4-ylethyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 648 (MH)⁺

iv)3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N-(2-morpholin-4-ylethyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.22 min, ES+ve 608 (MH)⁺

Example 30N-[2-(2-Hydroxyethoxy)ethyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamidei)3-[4-({6-[(5R)-5-2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-N-[2-(2-hydroxyethoxy)ethyl]benzenesulfonamide

was prepared using methods similar to those described in Example 6 i.ES+ve 645 (MH)⁺

ii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-[2-(2-hydroxyethoxy)ethyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 647 (MH)⁻

iii)N-[2-(2-Hydroxyethoxy)ethyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide

was prepared using methods similar to those described in Example 14 v.LCMS RT=2.62 min, ES+ve 583 (MH)⁺

Example 31N-(4-Fluorophenyl)-3-(4-{[6-({(2R-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate i)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-N-(4-fluorophenyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.ES+ve 651 (MH)⁺

ii)3-[4-({6-[(5R-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-(4-fluorophenyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 655 (MH)⁺

iii)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-N-(4-fluorophenyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 629 (MH)⁺

iv)N-(4-Fluorophenyl)-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.81 min, ES+ve 589 (MH)⁺

Example 32N-[4-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate i)N-[4-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.ES+ve 712 (MH)⁺

ii)N-[4-(Aminosulfonyl)phenyl]-3-[4-({6-[(5R)-5-2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 716 (MH)⁺

iii)N-[4-(Aminosulfonyl)phenyl]-3-{4-[(6-{[(2R-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 690 (MH)⁺

iv)N-[4-(Aminosulfonyl)phenyl]-3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.61 min, ES+ve 650 (MH)⁺

Example 332-(Hydroxymethyl)-4-{(1R)-1-hydroxy-2-[(6-{4-[3-(piperazin-1-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethyl}phenolacetate i)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-({4-[3-(piperazin-1-ylsulfonyl)phenyl]but-3-ynyl}oxy)hexyl]-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 vii.ES+ve 626 (MH)⁺

ii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(piperazin-1-ylsulfonyl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one

was prepared using methods similar to those described in Example 1 viii.ES+ve 630 (MH)⁺

iii)(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(6-{4-[3-(piperazin-1-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethanol

was prepared using methods similar to those described in Example 1 ix.ES+ve 604 (MH)⁺

iv)2-(Hydroxymethyl)-4-{(R-1)-1-hydroxy-2-[(6-{4-[3-(piperazin-1-ylsulfonyl)phenyl]butoxy}hexyl)amino]ethyl}phenolacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.23 min, ES+ve 564 (MH)⁺

Example 343-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-N-(1-methyl-1-phenylethyl)benzenesulfonamideacetate i)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-N-(1-methyl-1-phenylethyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.ES−ve 673 (M−H)⁻

ii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-N-(1-methyl-1-phenylethyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES−ve 677 (M−H)⁻

iii)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]-amino}hexyl)oxy]butyl}-N-(1-methyl-1-phenylethyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 653 (MH)⁺

iv)3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-N-(1-methyl-1-phenylethyl)benzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.90 min, ES+ve 613 (MH)⁺

Example 355-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-hydroxymethyl)-phenyl]ethyl}amino)hexyl]oxy}butyl)-2-methoxybenzenesulfonamideacetate i)5-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-2-methoxybenzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.ES+ve 587 (MH)⁺

ii)5-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-2-methoxybenzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 591 (MH)⁺

iii)5-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-2-methoxybenzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 565 (MH)⁺

iv)5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-2-methoxybenzenesulfonamideacetate

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.41 min, ES+ve 525 (MH)⁺

Example 36(E)-2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-N-methylethenesulfonamidei) 4-(3-Bromophenyl)but-3-yn-1-ol

A stirred, cooled solution of 1-bromo-3-iodobenzene (31 g) and3-butyn-ol (7 ml) in acetonitrile (100 ml) and triethylamine (100 ml)was purged with nitrogen for 20 min under nitrogen.Dichlorobis(triphenylphosphine)palladium (500 mg) and cuprous iodide(800 mg) were added. The mixture was stirred for 18 h and then thesolvent was removed in-vacuo. The residual oil was triturated with ethylacetate (200 ml) and filtered. The filtrate was evaporated to drynessand the residue was purified by chromatography on Biotage (90 g) elutingwith light petroleum 40-60°-diethyl ether (3:2) to give the titlecompound (21 g). LCMS RT=3.26 min.

ii) 4-(3-Bromophenyl)butan-1-ol

A solution of 4-(3-bromophenyl)but-3-yn-1-ol (21 g) in ethanol (1000 ml)was hydrogenated over platinum oxide (500 mg) for 4 h. The catalyst wasremoved by filtration and the filtrate was evaporated to give the titlecompound (18 g) tlc (SiO₂) diethyl ether R_(f)=0.38.

iii) 1-Bromo-3-{4-[(6-bromohexyl)oxy]butyl}benzene

A stirred mixture of 4-(3-bromophenyl)butan-1-ol (18 g) and 1,6dibromohexane (48 ml) in 50% aq. sodium hydroxide (500 ml) withtetrabutylammonium bromide (1.5 g) was stirred for 2 d at 20°. Themixture was poured into water (1000 ml) and extracted into ethyl acetate(3×500 ml). The combined extracts were washed with water (1000 ml),dried (Na₂SO₄). The solvent was removed in-vacuo and the residual oilwas purified by flash chromatography (500 g) using dichloromethane aseluent, changing to light petroleum (40-60°)-diethyl ether (9:1) to givethe title compound (18 g). LCMS RT=4.34 min.

iv)(5R)-3-{6-[4-(3-Bromophenyl)butoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

Sodium hydride (60% dispersion in oil, 690 mg) was added to a stirredsolution of5R-(2,2-dimethyl-4H-1,3-benzodioxin-6yl)-1,3-oxazolidin-2-one (3.0 g) indry DMF (35 ml) at 5° C. under nitrogen. After 20 min a solution of1-bromo-3-{4-[(6-bromohexyl)oxy]butyl}benzene (5.64 g) in dry DMF (15ml) was added. The mixture was stirred at ambient temperature for 4 h.The mixture was poured into an ammonium chloride solution (300 ml) andextracted into ethyl acetate (3×100 ml). The combined extracts werewashed with water (200 ml), dried (Na₂SO₄) and evaporated. The residualoil was purified by chromatography on Biotage (90 g) eluting withdiethyl ether-light petroleum (bp 40-60) (4:1) to give the titlecompound (5.2 g). LCMS RT=4.13 min.

v)(E)-2-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}-N-methylethenesulfonamide

A stirred mixture(5R)-3-{6-[4-(3-bromophenyl)butoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(1.0 g), N-methylethenesulphonamide (WO 95/09166), (462 mg),tri-o-tolylphosphine (200 mg), palladium acetate (165 mg) andtriethylamine (5 ml) in dry DMF (15 ml) was heated at 90° C. for 18 h.The mixture was cooled and filtered. The filtrate was poured into water(200 ml) and extracted into ethyl acetate (3×50 ml). The combinedextracts were washed with water (100 ml) and (Na₂SO₄) and evaporated invacuo. The residual oil was purified by chromatography on Biotage (40 g)eluting with diethyl ether-ethyl acetate (9:1) to give the titlecompound (220 mg). LCMS RT=3.70 min.

vi)(E)-2-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-N-methylethenesulfonamide

Was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.96 min

vii)(E)-2-[3-(4-{[6-({(2R-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-N-methylethenesulfonamide

A solution of(E)-2-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-N-methylethenesulfonamide(100 mg) in methanol (15 ml) was administered onto a Bond Elut SCX2cartridge (10 g), which had been preconditioned in methanol. Thecartridge was eluted with methanol (2×25 ml) followed by 15% aq.ammonia-methanol (2×20 ml). Evaporation of the latter fractions gave thetitle compound (70 mg) LCMS RT=2.59 min, ES+ve 535 (MH)⁺

viii)(E)-2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-N-methylethanesulfonamideCompound with (2E)-but-2-enedioic acid (1:1)

A solution of(E)-2-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-N-methylethenesulfonamide(60 mg) and fumaric acid (6.5 mg) in ethanol was evaporated to drynessto give the title compound (66 mg) LCMS RT=2.65 min, ES+ve 537 (MH)⁺

Example 372-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]ethanesulfonamidei) tert-Butyl vinylsulfonylcarbamate

Di-tert-butyidicarbonate (8.62 g) was added to a stirred, cooled (icebath) solution of ethenesulphonamide (S. Hirooka, Bull. Chem. Soc. Jpn.1991, 64, 1431) (3.4 g), 4-(dimethylamino)pyridine (410 mg) andtriethylamine (7 ml) in dichloromethane (40 ml) under nitrogen. Thesolution was stirred for 30 min, washed with 2M hydrochloric acid (30ml), water (50 ml) and dried (Na₂SO₄) to give the title compound (5.0g). Tlc (SiO₂, 1:1 diethyl ether-cyclohexane) Rf=0.4.

ii)(E)-2-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}ethenesulfonamide

Was prepared using methods similar to those described in Example 36 v.LCMS RT=3.6 min

iii)(E)-2-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)ethenesulfonamide

Was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.87 min

iv)(E)-2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]ethenesulfonamide

Was prepared using methods similar to those described in Example 1 x.LCMS RT=2.55 min

v)2-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]ethanesulfonamide

Was prepared using methods similar to those described in Example 1 viii.LCMS RT=2.73 min, ES+ve 523 (MH)⁺

Example 385-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)[1,1′-biphenyl]-3-sulfonamideacetate i) tert-Butyl(3,5-diiodophenyl)sulfonylcarbamate

Di tert-butyl dicarbonate (1.11 g) was added to a stirred solution of3,5 di-iodo-benzenesulfonamide (Tsatsas, Chem. Chron. 1974, 3, 143) (1.6g), 4-dimethylamino)pyridine (50 mg) and triethylamine (0.8 ml) indichloromethane (30 ml) at 5°. The solution was stirred at ambienttemperature for 1 h, washed with 1M hydrochloric acid (30 ml), water (50ml) and dried (Na₂SO₄). The solvent was evaporated to give the titlecompound (1.6 g). LCMS RT=4.24 min.

ii)tert-Butyl(3,5-diiodophenyl)sulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate

Sodium hydride (60% dispersion in oil, 157 mg) was added to a stirredsolution of tert-butyl(3,5-diiodophenyl)sulfonylcarbamate (1.6 g) in DMF(10 ml) at 5° under nitrogen. After 10 min2-(trimethylsilyl)ethoxymethyl chloride (0.61 ml) was added. The mixturewas stirred for 30 min. The reaction mixture was poured into aq.ammonium chloride (100 ml) and extracted into diethyl ether (3×40 ml).The organic extracts were washed with water (30 ml), dried (Na₂SO₄) andevaporated to give the title compound (1.95 g). LCMS RT=4.47 min.

iii) tert-Butyl{3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-5-iodophenyl}sulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate

A solution of (5R)3-[6-but-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(233 mg) andtert-butyl(3,5-diiodophenyl)sulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate(410 mg) in dry acetonitrile (3 ml) and triethylamine (3 ml) was purgedwith nitrogen for 30 min. Cuprous iodide (50 mg) anddichlorobis(triphenylphosphine)palladium (50 mg) were then added. Themixture was stirred for 18 h at ambient temperature and then evaporatedto dryness. The residual oil was purified by chromatography on Biotage(8 g) eluting with diethyl ether-petroleum ether (bp 40-60°). Theappropriate fractions were evaporated to give the title compound (190mg). LCMS RT=4.54 min.

iv)3-[((tert-Butoxycarbonyl){[2-(trimethylsilyl)ethoxy]methyl}amino)sulfonyl]-5-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-1,1′-biphenyl

A stirred mixture of tert-butyl{3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-5-iodophenyl}sulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate(190 mg), benzeneboronic acid (62 mg) in dimethoxyethane (4 ml) and 1Msodium carbonate (2 ml) with tetrakis(triphenylphosphine)palladium(0)(25 mg) was heated at 80° for 1 h. The mixture was poured into water (20ml) and extracted into ethyl acetate (3×30 ml). The organic extractswere dried (Na₂SO₄) and evaporated. The residual oil was purified bychromatography on Biotage (8 g) eluting with cyclohexane-diethyl ether(4:1) to give the title compound (140 mg). LCMS RT=4.54 min.

v)3-[((tert-Butoxccarbonyl){[2-(trimethylsilyl)ethoxy]methyl}amino)sulfonyl]-5-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-1,1′-biphenyl

was prepared using methods similar to those described in Example 1 viii.LCMS RT=4.55 min.

vi)5-{4-[(6-{[(2R-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}[1,1′-biphenyl]-3-sulfonamide

Was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.86 min.

vii)5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)[1,1′-biphenyl]-3-sulfonamideacetate

Was prepared using methods similar to those described in Example 1 x.LCMS RT=2.76 min, ES+ve 571(MH)⁺.

Example 393-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-5-pentylbenzenesulfonamideacetate i) tert-Butyl{3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-5-pent-1-ynylphenyl}sulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate

Was prepared using methods similar to those described in Example 1 vii.LCMS RT=4.77 min.

ii) tert-Butyl{3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-5-pentylphenyl}sulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate

Was prepared using methods similar to those described in Example 1 viii.LCMS RT=4.7 min.

iii)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-5-pentylbenzenesulfonamide

Was prepared using methods similar to those described in Example 1 ix.LCMS RT=3.21 min.

iv)3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)-5-pentylbenzenesulfonamideacetate

Was prepared using methods similar to those described in Example 1 xLCMS RT=2.93 min, ES+ve 565 (MH)⁺

Example 403-(4-{[6-({(2R)-2Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}aminohexyl]oxy}butyl)benzenesulfonamide(i) 6-(But-3-ynyloxy)hexanal

6-Bromohexylbut-3-ynyl ether (DE3513885A1) (525 mg) in DMSO (2 ml) wasadded to a mixture of sodium bicarbonate (1 g) in DMSO (8 ml) at 150° C.with vigorous stirring and nitrogen bubbling through the solution. Themixture was stirred for 20 min at 150° C. and then allowed to cool toroom temperature, diluted with diethyl ether and washed with water. Theaqueous layer was extracted with diethyl ether and the combined etherlayers were washed with dilute hydrochloric acid, brine, dried (MgSO₄)and evaporated to dryness to give the title compound (325 mg): IR 1726cm⁻¹ MS(TSP+ve) m/z 186 (M+MH₄)⁺.

(ii)(1R)-2-{[6-(But-3-ynyloxy)hexyl][(1S)-2-hydroxy-1-phenylethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

A mixture of 6-(but-3-ynyloxy)hexanal (434 mg) and(1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethanol(710 mg) (WO/0196278) in chloroform (10 ml) was treated at 20° C. withsodium triacetoxyborohydride (866 mg) and stirred under nitrogen for 2days. The mixture was diluted with ethyl acetate and aqueous sodiumbicarbonate solution. The organic phase was separated and washed withsodium bicarbonate solution, brine, dried and purified on a silica BondElut cartridge (10 g) eluting with dichloromethane, diethyl ether andfinally ethyl acetate to give the title compound (810 mg): LCMS RT=2.69min, ES+ve m/z 496 (M+H)⁺.

(iii)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl][(1S)-2-hydroxy-1-phenylethyl]amino}hexyl)oxy]but-1-ynyl}benzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=2.85 min

(iv)3-(4-{[6-({(2R)-2Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}aminohexyl]oxy}butyl)benzenesulfonamide

3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl][(1S)-2-hydroxy-1-phenylethyl]amino}hexyl)oxy]but-1-ynyl}benzenesulfonamide(104 mg) was hydrogenated in ethanol (50 ml) over Pearlman's catalyst(60 mg) over 4 h and then over 10% Pd/C (100 mg) over 4 days. Thecatalyst was removed by filtration and washed with ethanol. The filtratewas concentrated and then applied to an SCX-2 cartridge eluting withmethanol, followed by 0.67M ammonia in methanol. The ammonia fractionswere concentrated and purified by chromatography on Biotage (4 gcartridge) eluting with dichloromethane-methanol-2M ammonia in methanol(50:8:1) to give the title compound (11 mg) LCMS RT=2.34 min ES+ve 495(M+H)⁺.

Example 413-Fluoro-5-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamidei) 3-Fluoro-5-iodobenzenesulfonamide

3-Fluoro-5-iodoaniline (3.06 g) (WO 9623783) was added to a stirredmixture of concentrated hydrochloric acid (4 ml) and water (4 ml).Glacial acetic acid (8 ml) was added and the reaction mixture cooled to−5° C. A solution of sodium nitrite (0.99 g) in water (8 ml) was addeddropwise maintaining the temperature between −5° C. and −2° C. After theaddition was complete the reaction was stirred for 10 min. In themeantime glacial acetic acid (20 ml) was saturated with sulfur dioxidegas for 0.25 h, then copper(I) chloride (0.353 g) was added. Additionalsulfur dioxide was bubbled through the solution until a fine suspensionwas obtained. The mixture was cooled to 5° C. and then treatedportionwise with the diazonium salt prepared above. After stirring atroom temperature for 1 h ice (50 g) was added. The mixture was extractedwith ether (100 ml) and the organic phases washed with NaHCO₃ solution(2×100 ml) then water (100 ml), dried (MgSO₄) and concentrated. Theresidue was dissolved in THF (30 ml) at 0° C. and aqueous ammonia(0.880; 5 ml) was added. After stirring at room temperature the mixturewas partitioned between EtOAc (100 ml) and water (100 ml). The organicphase was washed with brine (50 ml), dried (MgSO₄) and concentrated. Theresidue was purified by chromatography using cyclohexane-EtOAc (5:1 then3:1). Evaporation of the fractions and trituration of the residue withcyclohexane afforded the title compound (0.886 g). ES−ve 299 (M−H)⁻

ii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-5-fluorobenzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.ES+ve 575 (MH)⁺

iii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-5-fluorobenzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 579 (MH)⁺

iv)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl-2-hydroxyethyl]amino}hexyl)oxy]butyl}-5-fluorobenzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 553 (MH)⁺

v)3-Fluoro-5-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide

was prepared using methods similar to those described in Example 36 vii.LCMS RT=2.50 min, ES+ve 513 (MH)⁺

Example 425-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-3-trifluoromethylbenzenesulfonamidei) 3-Bromo-5-trifluoromethylbenzenesulfonamide

was prepared using methods similar to those described in Example i.ES−ve 302,304 (M−H)⁻

ii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-5-(trifluoromethyl)benzenesulfonamide

was prepared using methods similar to those described in Example 6 i.ES+ve 625 (MH)⁺

iii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-5-trifluoromethylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.ES+ve 629 (MH)⁺

iv)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-5-(trifluoromethyl)benzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.ES+ve 603 (MH)⁺

v)3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-5-(trifluoromethyl)benzenesulfonamide

was prepared using methods similar to those described in Example 36 vii.LCMS RT=2.57 min, ES+ve 563 (MH)⁺

Example 433-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-5-methylbenzenesulfonamideacetate i) 3-Bromo-5-methylbenzenesulfonamide

was prepared from 3-bromo-5-methylaniline (EP303387A1) using methodssimilar to those described in Example 41(i). LCMS RT=2.80 min

ii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]-5-methylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 vii.LCMS RT=3.54 min

iii)3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]-5-methylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 viii.LCMS RT=3.60 min

iv)3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}-5-methylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 ix.LCMS RT=2.73 min

v)3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-5-methylbenzenesulfonamide

was prepared using methods similar to those described in Example 1 x.LCMS RT=2.43 min, ES+ve 509 (MH⁺)

Example 44N-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}glycineacetate N²-[(3-Iodophenyl)sulfonyl]glycinamide

(3-Iodophenyl)sulphonyl chloride (0.303 g) was stirred with glycinamidehydrochloride (0.122 g) and diisopropylethylamine (0.3 ml) in DMF (4 ml)at 21° for 24 h. The mixture was evaporated to dryness and applied to asilica Bond Elut Cartridge (10 g). The cartridge was eluted with CH₂Cl₂,Et₂O and EtOAc. This gave the title compound (0.146 g), LCMS RT=2.36min, ES+ve 341 (MH)⁺

ii)N²-({3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}sulfonyl)glycinamide

was prepared using methods similar to those in Example 1 vii LCMSRT=3.26 min, ES+ve 614 (MH)⁺

iii)N²-({3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}sulfonyl)glycinamide

was prepared using methods similar to those in Example 1 viii LCMSRT=3.23 min, ES+ve 618 (MH)⁺

iv)N-[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]glycine

was prepared using methods similar to those in Example 1 ix LCMS RT=2.70min, ES+ve 593 (MH)⁺

v)N-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}glycineacetate

was prepared using methods similar to those in Example 1 x LCMS RT=2.38min, ES+ve 553 (MH)⁺

Example 453-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide(i) 6-Bromohexyl but-3-ynyl ether

A mixture of 50% w/v aqueous sodium hydroxide (2500 ml),1,6-dibromohexane (2610 g) and tetra-butylammonium bromide (25 g) waswarmed to 50° C., with stirring. But-3-yn-1-ol (500 g) was then added tothe reaction mixture at such a rate as to ensure the content'stemperature did not exceed 65° C. The reaction was left at 50° C.overnight before being cooled to room temperature. Tert-butyl methylether (2500 ml) and brine (2000 ml) was added to the cooled mixture andthe layers allowed to separate. The ethereal layer was washed with water(2×2000 ml), brine (1×2000 ml), and then dried over anhydrous MgSO₄. Thesolution was filtered and concentrated under reduced pressure to givecrude product as a liquid. This was further purified by fractionaldistillation using a 60 cm vacuum jacketed Vigreux column at ca. 0.5mbar. The product was obtained in the fraction which boiled at 92-98°C., to give the title compound (518 g), LC RT=6.16, δ (CDCl₃) 3.55 (2H,t, J 6.9 Hz), 3.46 (2H, t, J 6.9 Hz), 3.41 (2H, t, J 6.9 Hz), 2.46 (2H,dt, J 2.5, 6.9 Hz), 1.98 (1H, t, J 2.5 Hz), 1.86 (2H, m), 1.59 (2H, m),1.46 (2H, m), 1.38 (2H, m).

(ii) 3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}benzenesulfonamide

A mixture of 3-bromo-benzenesulfonamide (625 g), 6-bromohexyl but-3-ynylether (850.1 g), bis(triphenylphosphine)palladium (II) chloride (62.5g), triphenylphosphine (18.1 g) and triethylamine (536.3 g) intetrahydrofuran (6250 ml) was stirred under an atmosphere of nitrogenfor 20 mins. Copper(I) iodide (12.5 g) was then added to give a darkred/brown mixture that was heated to 50° C. for 23 h. The reactionmixture was then cooled to room temperature and filtered through a shortsilica pad (1000 g). The pad was washed with additional tetrahydrofuran(15.6 L) and the resulting solution then concentrated under reducedpressure to give crude product (1382 g) as a viscous oil. This waspurified by chromatography (7 kg silica) eluting with 5:1 petroleumether:ethyl acetate followed by 2:1 petroleum ether:ethyl acetate togive the title compound (932.9 g) as an oil, LC RT=5.69 min, δ (DMSO-d₆)7.79 (1H, s), 7.76 (1H, d, J 7.6 Hz), 7.56 (2H, m), 7.42 (2H, m), 3.55(2H, t, J 6.6 Hz), 3.49 (2H, t, J 6.6 Hz), 3.42 (2H, t, J 6.6 Hz), 2.68(2H, t, J 6.6 Hz), 1.76 (2H, m), 1.50 (2H, m), 1.35 (4H, m).

(iii) 3-{4-[(6-Bromohexyl)oxy]butyl}benzenesulfonamide

3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}benzenesulfonamide (627 g) in IMS(1900 ml) was stirred with activated charcoal (314 g) at roomtemperature for 2 h and then filtered through a short pad of Celite. Thefilter pad was washed with IMS (4300 ml) and the filtrate transferred toa hydrogenation vessel. 5% Platinum on Charcoal (520.1 g, 50% water) wasadded and the reaction mixture was then stirred under an atmosphere ofhydrogen (0.2 bar) at 20° C. for 6 h. The mixture was then filteredthrough a short pad of Celite and concentrated under reduced pressure togive the title compound (499 g) as a solid, LC RT=5.66, δ (DMSO-d₆) 7.65(1H, s), 7.64 (1H, d, J 9.2 Hz), 7.47 (1H, m), 7.42 (1H, m), 7.31 (2H,s), 3.50 (2H, t, J 6.9 Hz), 3.34 (4H, m), 2.66 (2H, t, J 7.5 Hz), 1.78(2H, m), 1.62 (2H, m), 1.49 (4H, m), 1.37 (2H, m), 1.30 (2H, m).

(iv) (1R) 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

A solution R-diphenylprolinol (75 mg) in THF (2 ml) was treated withborane-THF (1M, 20.5 ml) over 20 min at 20° C. under nitrogen. After theaddition was complete the solution was kept between 30 and 35° C. for 1h and then cooled in ice and2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (DE3513885)(3.9 g) in THF (10 ml) was added over 1.5 h keeping the temperaturebelow 5° C. The mixture was stirred under nitrogen for a further 0.5 hand then methanol (4 ml) was added at 0° C. The solvent was removedunder reduced pressure and the residue was purified by chromatography onflash silica gel eluting with ethyl acetate-cyclohexane (1:4) to givethe title compound (3.31 g) δ (CDCl₃) 7.15 (1H, dd, J 8, 2 Hz), 7.03(1H, br s), 6.82 (1H, d, J 8 Hz), 4.85 (3H, s and m), 3.61 (1H, dd, J10, 4 Hz), 3.50 (1H, dd, J 10, 9 Hz), 1.54 (6H, s).

(v){[(1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethyl]oxy}(triethyl)silane

Triethylsilyl chloride (205 g) was added dropwise to a stirred mixtureof (1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (350 g)and imidazole (108.5 g) in DMF (875 ml) at 5° C. Upon complete additionthe mixture was warmed to 15° C. and stirred, at this temperature for 1h. N-hexane (3500 ml) was then added to the mixture which was washedwith water (3×1750 ml). The organic layer was dried over anhydrous MgSO₄before being filtered and concentrated under reduced pressure to givethe title compound (488.6 g) as an oil, LC RT=7.97 min, δ (DMSO-d₆) 7.18(1H, d, J 8.2 Hz), 7.10 (1H, s), 6.75 (1H, d, J 8.2 Hz), 4.83 (1H, m),4.78 (2H, d, J 6.9 Hz), 3.55 (2H, m), 1.45 (6H, s), 0.84 (9H, t, J 8.1Hz), 0.51 (6H, m).

(vi)N-benzyl-N-{(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(triethylsilyl)oxy]ethyl}amine

A mixture of{[(1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethyl]oxy}(triethyl)silane(130 g) and benzylamine (177 ml) in 1,4-dioxane (650 ml) was heated at105° C. with stirring overnight. The mixture was then cooled to roomtemperature and water (150 ml) and diethyl ether (1200 ml) added. Thelayers were separated and the ethereal layer was washed with saturatedammonium chloride solution (3×600 ml), saturated sodium bicarbonatesolution (200 ml) and then brine (200 ml). The solution was dried overanhydrous Na₂SO₄ before being filtered and concentrated under reducedpressure to give the title compound (129.9 g) as an oil, LC RT=5.20 min,δ (CDCl₃) 7.22 (5H, m), 7.02 (1H, d, J 8.7 Hz), 6.86 (1H, s), 6.68 (1H,d, J 8.3 Hz), 4.75 (2H, s), 4.69 (1H, m), 3.73 (2H, s), 2.70 (2H, m),1.46 (6H, s), 0.79 (9H, m), 0.44 (6H, m).

(vii)(1R)-2-(Benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Tetrabutylammonium fluoride (395 ml, 1M in THF) was added dropwise to astirred solution ofN-benzyl-N-{(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(triethylsilyl)oxy]ethyl}amine(129.9 g) in THF (900 ml) at 5° C. Upon complete addition the reactionmixture was maintained at this temperature for 15 min before water (600ml) was added. The resulting slurry was diluted with diethyl ether (500ml) and filtered. The filtrate was washed with water (2×500 ml) andbrine (500 ml) before being dried over anhydrous Na₂SO₄. The resultingmixture was filtered and concentrated under reduced pressure to give asolid which was triturated with diisopropyl ether to give the titlecompound (70 g) as a solid, LC RT=3.34 min, δ (CDCl₃) 7.31 (5H, m), 7.09(1H, d, J 8 Hz), 6.98 (1H, s), 6.77 (1H, d J 8 Hz), 4.82 (2H, s), 4.63(1H, m), 3.83 (2H, d, J 4 Hz), 2.80 (2H, m), 1.52 (6H, s).

(viii)3-{4-[(6-{Benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide

A stirred mixture of 3-{4-[(6-bromohexyl)oxy]butyl}benzenesulfonamide(11.1 g),(1R)-2-(benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (9g) and diisopropyl ethylamine (8.9 ml) in acetonitrile (28 ml) washeated at reflux for 18 h. The resulting mixture was cooled to roomtemperature, diluted with diethyl ether (250 ml) and washed with water(2×100 ml) and brine (100 ml) before being dried over anhydrous Na₂SO₄.The suspension was filtered and concentrated under reduced pressure togive the title compound (20 g) as an oil. LC RT=4.68 min, δ (CDCl₃) 7.70(2H, m), 7.38 (2H, m), 7.29 (5H, m), 7.02 (1H, d, J 8.3 Hz), 6.91 (1H,s), 6.73 (1H, d, J 8.3 Hz), 4.79 (2H, s), 4.53 (1H, m), 3.87 (1H, m),3.40 (5H, m), 2.69 (2H, t, J 7.2 Hz), 2.54 (2H, m), 2.43 (2H, m), 1.70(2H, m), 1.60 (2H, m), 1.51 (10H, m), 1.25 (4H, m)

(ix)3-(4-{[6-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide

Hydrochloric acid (80 ml, 1M) was added dropwise to a stirred solutionof3-{4-[(6-{benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide(20 g) in ethanol (100 ml) at 0° C. Upon complete addition the mixturewas stirred at 5° C. for 1 h before being allowed to warm to roomtemperature. A portion (50 ml) of the ethanol was removed under reducedpressure and the remaining mixture was diluted with ethyl acetate (250ml). The mixture was then washed with water (100 ml), saturated sodiumbicarbonate solution (100 ml) and brine (100 ml) before being dried overanhydrous Na₂SO₄. The suspension was filtered and concentrated underreduced pressure to give the title compound (16 g) as an oil. LC RT=4.02min, δ (DMSO-d₆) 9.15 (1H, s), 7.65 (1H, s), 7.64 (1H, d, J 8.8 Hz),7.45 (2H, m), 7.27 (8H, m), 6.94 (1H, dd, J 8.2 Hz), 6.67 (1H, d, J 8.2Hz), 4.92 (1H, t, J 5.7 Hz), 4.67 (1H, s), 4.56 (1H, m), 4.45 (2H, d, J5.7 Hz), 3.61 (2H, m), 3.34 (2H, t, J 6.3 Hz), 3.28 (2H, t, J 6.2 Hz),2.66 (2H, m), 2.50 (2H, m), 2.39 (2H, m), 1.61 (2H, m), 1.50 (2H, m),1.39 (4H, m), 1.16 (4H, m).

(x)3-(4-{[6-({(2R-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide

5% Pd/C (8 g, 50% wet) was added to a solution of3-(4-{[6-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide(16 g) in IMS and the mixture was stirred under hydrogen for 6 h. Theresulting suspension was filtered through a plug of Celite which wasthen washed with IMS (160 ml). The combined washings were concentratedunder reduced pressure to give the title compound (12.8 g) as an oil, LCRT=3.51 min, δ (CD₃OD) 7.64 (1H, s), 7.61 (1H, m), 7.33 (2H, m), 7.20(1H, s), 7.01 (1H, dd, J 2.2, 8.2 Hz), 6.65 (1H, d, J 8.2 Hz), 4.61 (1H,m), 4.54 (2H, s), 3.33 (4H, m), 2.72 (2H, m) 2.63 (2H, m), 2.57 (2H, m)1.62 (2H, m), 1.46 (6H, m), 1.27 (4H, m).

Example 46

The following salts of the compound of Example 45 were prepared asdescribed below.

(i) Cinnamate Salt

Cinnamic acid (0.3 g) was added to a solution of3-(4-{[6-({(2R-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide(1.0 g) in methanol (5 ml) at room temperature. The solution was stirredfor 5 minutes before being concentrated under reduced pressure to give apale yellow gum. Water (10 ml) was added to the gum and the reultingsuspension stirred at room temperature for 24 h. The suspension was thenfiltered to give the title compound as a white solid (0.72 g), which wasthen recrystallised from ethanol (5 ml) to give a white solid (0.54 g)mp 127-128° C., δ (CD₃OD) 7.73 (1H, s), 7.71 (1H, d, J 7.5 Hz), 7.50(2H, d, 37 Hz), 7.41 (3H, m), 7.32 (4H, m), 7.16 (1H, dd, J 2.2, 8.2Hz), 6.78 (1H, d, J 8.2 Hz), 6.49 (1H, d, 316.4 Hz), 4.88 (1H, dd, J3.8, 9.5 Hz), 4.65 (2H, s), 3.40 (4H, m), 3.10 (2H, m) 2.99 (2H, m),2.69 (2H, t, J 7.5 Hz) 1.68 (4H, m), 1.55 (4H, m), 1.39 (4H, m).

(ii) 1-Hydoxynaphthoate Salt

Was prepared using methods similar to those quoted above, isolation frommethanol/water gave the title compound as a white solid mp 60-69° C., δ(CD₃OD) 8.28 (1H, d, J 8.2 Hz), 7.85 (1H, d, J 8.8 Hz), 7.72 (3H, m),7.48 (1H, m), 7.39 (4H, m), 7.19 (1H, d, J 8.8 Hz), 7.16 (1H, d, J 8.2Hz), 6.78 (1H, d, J 8.2 Hz), 4.88 (1H, m), 4.65 (2H, s), 3.35 (4H, m),3.10 (2H, m) 2.99 (2H, m), 2.66 (2H, t, J 7.5 Hz) 1.65 (4H, m), 1.51(4H, m), 1.34 (4H, m).

(iii) 4-Phenylbenzoate Salt

Was prepared using methods similar to those quoted above, isolation frommethanol/water gave the title compound as a white solid mp 134-136° C.,δ (CD₃OD) 8.01 (2H, d, J 8.1 Hz), 7.73 (1H, s), 7.70 (1H, d, J 6.9 Hz),7.62 (4H, m), 7.43 (4H, m), 7.34 (2H, m), 7.16 (1H, dd, J 2.6, 8.1 Hz),6.78 (1H, d, J 8.1 Hz), 4.86 (1H, m), 4.64 (2H, s), 3.42 (4H, m), 3.08(2H, m) 2.98 (2H, t, J 7.5 Hz), 2.71 (2H, t, J 7.5 Hz) 1.70 (4H, m),1.57 (4H, m), 1.40 (4H, m).

(iv) Triphenylacetate Salt

Was prepared using methods similar to those quoted above, isolation frommethanol/water gave the title compound as a white solid mp 99-102° C., δ(CD₃OD) 7.74 (1H, s), 7.70 (1H, d, J 6.2 Hz), 7.42 (2H, m), 7.32 (1H,s), 7.27 (6H, m), 7.19 (6H, m), 7.13 (4H, m), 6.77 (1H, d, J 8.2 Hz),4.85 (1H, dd, J 4.4, 9.4 Hz), 4.65 (2H, s), 3.42 (4H, m), 3.04 (2H, m)2.94 (2H, t, J 7.5 Hz), 2.72 (2H, t, J 7.5 Hz) 1.70 (4H, m), 1.57 (4H,m), 1.40 (4H, m).

(v) 4-Methyl Cinnamate Salt

Was prepared using methods similar to those quoted above, isolation frommethanol/water gave the title compound as a white solid mp 110-113° C.,δ (CD₃OD) 7.73 (1H, s), 7.71 (1H, d, J 7.5 Hz), 7.39 (6H, m), 7.16 (3H,m), 6.78 (1H, d, J 8.2 Hz), 6.45 (1H, d, J 15.7 Hz), 4.88 (1H, dd, J3.8, 10.0 Hz), 4.65 (2H, s), 3.40 (4H, m), 3.10 (2H, m) 2.99 (2H, m),2.68 (2H, t, J 7.5 Hz) 2.31 (3H, s), 1.68 (4H, m), 1.55 (4H, m), 1.39(4H, m).

(vi) 4-Methoxy Cinnamate Salt

Was prepared using methods similar to those quoted above, isolation frommethanol/water gave the title compound as a white solid mp 115-118° C.,δ (CD₃OD) 7.73 (1H, s), 7.71 (1H, d, J 6.9 Hz), 7.40 (5H, m), 7.35 (1H,s), 7.16 (1H, d, J 8.2 Hz), 6.89 (2H, d, J 8.8 Hz) 6.78 (1H, d, J 8.8Hz), 6.37 (1H, d, J 16.4 Hz), 4.88 (1H, dd, J 3.2, 10.0 Hz), 4.65 (2H,s), 3.78 (3H, s), 3.40 (4H, m), 3.10 (2H, m) 2.99 (2H, m), 2.68 (2H, t,J 7.5 Hz) 1.68 (4H, m), 1.55 (4H, m), 1.39 (4H, m).

(vii) 3-(2-Naphthalenyl)-2-propanoate Salt

Was prepared using methods similar to those quoted above, isolation frommethanol/water gave the title compound as a white solid mp 139-144° C.,δ (CD₃OD) 7.91 (1H, s), 7.83 (3H, m), 7.72 (3H, m), 7.59 (1H, d, J 15.7Hz), 7.47 (2H, m), 7.41 (2H, m), 7.34 (1H, s), 7.16 (1H, dd, J 2.5, 8.1Hz), 6.78 (1H, d, J 8.1 Hz), 6.62 (1H, d, J 16.4 Hz), 4.85 (1H, m), 4.65(2H, s), 3.40 (4H, m), 3.08 (2H, m) 2.98 (2H, m), 2.70 (2H, t, J 7.5 Hz)1.69 (4H, m), 1.56 (4H, m), 1.39 (4H, m).

Example 473-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide(i) 7-Bromoheptyl prop-2-ynyl ether

25% (w/w) aq. NaOH (700 ml) was added to a stirred mixture of propargylalcohol (70 g), tetra-butyl ammonium bromide (3.5 g) and1,7-dibromoheptane (322 g) maintaining the temperature below 30° C. Thereaction mixture was heated at 60° C. for 5 hrs then allowed to cool toroom temperature and stirred overnight. Diethyl ether (350 ml) and water(280 ml) were added, the mixture stirred and allowed to settle. Theaqueous layer was extracted with diethyl ether (210 ml), the organiclayers combined, dried (MgSO₄). The solution was concentrated to give280 g of crude material. 140 g Of the crude was purified bychromatography on Biotage (800 g) eluting with petroleum ether thenpetroleum ether:ethyl acetate (100:1 followed by 100:1.5) to give thetitle compound (49.6 g). NMR—300 MHz—δ (CDCl₃)—4.05 (2H, d, J 2 Hz),3.45 (2H, t, J 6.5 Hz), 3.35 (2H, t, J 7 Hz), 2.35 (1H, s), 1.8 (2H, m),1.5 (2H, m), 1.3 (4H, m).

(ii) 3-{3-[(7-Bromoheptyl)oxy]prop-1-ynyl}benzenesulfonamide

7-Bromoheptyl prop-2-ynyl ether (55.1 g) in THF (250 ml) was addeddropwise over ca 8 h to a stirred mixture of 3-bromobenzenesulfonamide(43.5 g), PdCl₂(PPh₃)₂ (6.48 g), PPh₃ (1.45 g), CuI (1.4 g) and Et₃N (52ml) in THF (250 ml) at 55±5° C. under nitrogen then the mixture heatedfor a further ca 15 hrs. The reaction was cooled, filtered throughCelite and the solids washed with THF. The solution was concentrated andthe product purified by chromatography on flash silica gel (600 g)eluting with petroleum ether:ethyl acetate (ratios ranging successivelyfrom 19:1 to 7:3) to give the title compound (33 g)—LC RT=5.85 min.NMR—300 MHz—δ (CDCl₃)—7.95 (1H, t, J 1.5 Hz), 7.78 (1H, dt, J 8, 2 Hz),7.55 (1H, dt, J 7.75, 2 Hz), 7.40 (1H, t, J 8 Hz), 5.0 (2H, br s), 4.3(2H, s), 3.4 (2H, t, J 6.5 Hz), 3.35 (2H, t, J 7.25 Hz), 1.75 (2H, m),1.55 (2H, m), 1.3 (4H, m).

(iii) 3-{3-[(7-Bromoheptyl)oxy]propyl}benzenesulfonamide

3-{3-[(7-Bromoheptyl)oxy]prop-1-ynyl}benzenesulfonamide (29.4 g) wasdissolved in Industrial Methylated Spirits (IMS) (300 ml). Nucharcharcoal (15 g, 50% w/w) was added and the suspension stirred at roomtemperature for ca 1.5 h. After filtering off the charcoal and washingthe filtrate with IMS (60 ml) the solution was then treated in twoseparate lots: 5% Pd/C catalyst (11.25 g, 50% wet) was added to each,the mixtures hydrogenated at atmospheric pressure and temperature for ca1-2 h, the catalyst filtered off, rinsed with IMS (ca 10 ml) and thefiltrate concentrated to give the crude product as a solid which wasrecrystallised from diisopropyl ether (100 ml) to give the titlecompound as a solid (15.1 g)—LC RT=5.91 min. NMR—300 MHz—δ (CDCl₃)—7.75(2H, m), 7.45 (2H, m), 4.9 (2H, br s), 3.42 (6H, m), 2.8 (2H, t, J 7.5Hz), 1.9 (4H, m), 1.65-1.55 (4H, m), 1.5-1.3 (4H, m).

(iv)3-{3-[(7-{Benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}benzenesulfonamide

A mixture of(1R)-2-benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol(55.8 g), 3-{3-[(7-bromoheptyl)oxy]propyl}benzenesulfonamide (63.65 g),N,N-diisopropylethylamine (55 ml) and acetonitrile (200 ml) was stirredand heated under N₂ at reflux for ca 21 h. The mixture was cooled toroom temperature then diethyl ether (1000 ml) and water (500 ml) wereadded and the mixture stirred. The organic phase was washed with water(500 ml), then saturated brine (500 ml) and dried (Na₂SO₄). The solutionwas concentrated and the product purified by chromatography on flashsilica gel (1000 g), eluting with petroleum ether:ethyl acetate (ratiosranging successively from 4:1 to 1:1) to give the title compound (97.7g)—LC RT=1.54 min. δ (DMSO-d₆)—7.75 (2H, m), 7.45 (1H, t, J 8 Hz), 7.4(1H, m), 7.35 (2H, s), 7.25 (5H, m), 7.05 (1H, d, J 8.5 Hz), 7.0 (1H,s), 6.7 (1H, d, J 8.5 Hz), 4.9 (1H, br s), 4.78 (2H, s), 4.6 (1H, m),3.65 (1H, d, J 13.8 Hz), 3.55 (1H, d, J 13.8 Hz), 3.4 (1H, br s), 3.3(4H, m), 2.7 (2H, m), 2.55 (2H, m), 2.4 (2H, m), 1.85 (2H, m), 1.45 (8H,m), 1.35 (2H, m), 1.25 (2H, m), 1.15 (4H, m).

(v)3-(3-{[7-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide

To a stirred, ice-cooled solution of3-{3-[(7-{Benzyl[(2R)-2-2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}benzenesulfonamide(97.2 g) in IMS (417 ml) was gradually added aqueous 1M hydrochloricacid (417 ml) keeping the temperature below 15° C. The mixture was thenstirred at room temperature for ca 5 h. Saturated sodium bicarbonate(417 ml) and ethyl acetate (1000 ml) were then added to the mixture. Theorganic layer was separated off, washed with water (400 ml), brine (400ml) and finally dried (Na₂SO₄). Concentration in vacuo gave the titlecompound (87.9 g)—LC RT=4.01 min. δ (CDCl₃)—7.75 (1H, br s), 7.70 (1H,m), 7.4-7.25 (8H, m), 7.0 (1H, d, J 8 Hz), 6.95 (1H, s), 6.75 (1H, d, J8 Hz), 4.7 (2H, s), 4.55 (1H, m), 3.9 (1H, d, J 13 Hz), 3.55 (1H, d, J13 Hz), 3.4 (4H, m), 2.75 (2H, t, J 7.5 Hz), 2.65 (1H, m), 2.55 (2H, d,J 7 Hz), 2.45 (1H, m), 1.87 (2H, m), 1.55 (4H, m), 1.3 (6H, m).

(vi)3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide

3-(3-{[7-(Benzyl{(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide(87.2 g) in methanol (800 ml) was hydrogenated over 5% Pd/C catalyst (28g, 50% wet) at atmospheric pressure and ambient temperature. Thecatalyst was removed by filtration through a Hyflo pad and the filtrateconcentrated in vacuo to give the title compound (64.4 g)—LC RT=3.46min. δ (DMSO-d₆)—7.65 (2H,m), 7.45 (2H, m), 7.25 (1H, s), 6.95 (1H, dd,J 8, 2 Hz), 6.67 (1H, d, J 8 Hz), 5.0 (2H, br m,), 4.45 (3H, m), 3.35(4H, m), 3.15 (2H, m), 2.7 (2H, m), 2.55-2.45 (4H, m), 1.8 (2H, m), 1.5(2H, m), 1.35 (2H, m), 1.25 (6H, m).

Example 48 (i)3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide(E)-3-(napthalen-2-yl)-2-propenoate

3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide(1 g) was taken up in ethanol (6 ml) at room temperature with stirringand (E)-3-(napthalen-2-yl)-2-propenoic acid (0.39 g) added. The mixturewas heated to ca 60° C. until a solution formed. The solution was cooledto room temperature and seed crystals of the title compound added. Themixture was aged for 65 h, the product filtered, washed with ethanol (1ml) and dried to give the title compound (1.05 g) M Pt.=135° C.-146° C.δ (MeOH-d₄) 7.95 (1H, s), 7.87 (3H, m), 7.75 (3H, m), 7.60 (1H, d, J 16Hz), 7.45 (5H, m), 7.40 (1H, m), 6.8 (1H, d, J 8 Hz), 6.65 (1H, d, J 16Hz), 4.9 (1H, m), 4.65 (2H, s), 3.4 (4H, m), 3.12 (2H, m), 3.05 (2H, brt, J 8 Hz), 2.75 (2H, t, J 8 Hz), 1.87 (2H, m), 1.72 (2H, m), 1.56 (2H,m), 1.40 (6H, m).

Alternatively:

3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzenesulfonamide(0.5 g), dissolved in methanol (10 ml) was treated with(E)-3-(napthalen-2-yl)-2-propenoic acid (0.194 g). The clear solutionwas evaporated to dryness and re-dissolved in ethanol (3 ml) and heatedto reflux. The solution was allowed to cool to room temperature andafter 48 h the product filtered, washed with ethanol (2 ml) and dried togive the title compound (0.58 g), M Pt 135-146° C.

(ii) 4-Phenylbenzoate Salt

In a similar fashion to the previous example, the title salt wasprepared (0.5 g). The XRPD pattern of this product is shown in FIG. 1. δ(MeOH-d₄) 8.05 (2H, d, J 8 Hz), 7.75 (2H, m), 7.65 (4H, m), 7.45 (4H,m), 7.35 (2H, m), 7.17 (1H, d, J 8 Hz), 6.8 (1H, d, J 8 Hz), 4.9 (s),4.65 (2H, s), 3.42 (4H, m), 3.12 (2H, m), 3.02 (2H, m), 2.80 (2H, t, J 8Hz), 1.90 (2H, m), 1.72 (2H, m), 1.55 (2H, m), 1.40 (2H, br s).

(iii) Triphenylacetate Salt

In a similar fashion, the title salt was prepared (0.485 g). The XRPDpattern of this product is shown in FIG. 2. δ (MeOH-d₄) 7.86 (2H, m),7.58 (2H, m), 7.48 (1H, m), 7.42 (6H, m), 7.35 (6H, m), 7.27 (4H, m),6.92 (1H, d, J 8 Hz), 5.00 (m), 4.78 (2H, s), 3.55 (4H, m), 3.50 (1H,s), 3.20 (2H, m), 3.10 (2H, m), 2.92 (2H, m), 2.05 (2H, m), 1.80 (2H,m), 1.72 (2H, m), 1.5 (6H, m).

(iv) 4-Phenylcinnamate Salt

In a similar fashion the title salt was prepared (0.243 g). The XRPDpattern of this product is shown in FIG. 3. δ (MeOH-d₄) 7.7 (2H, m),7.55 (6H, m), 7.35 (5H, m), 7.29 (2H, m), 7.1 (1H, d, J 8 Hz), 6.75 (1H,d, J 8 Hz), 6.56 (1H, d, J 15.5 Hz), 4.85 (m), 4.60 (2H, s), 3.35 (4H,m), 3.05 (2H, m), 2.95 (2H, m), 2.7 (2H, t, J 8 Hz), 1.8 (2H, m), 1.65(2H, m), 1.5 (2H, m), 1.3 (6H, br s).

(v) Sulphamate Salt

In a similar fashion the title salt was prepared (0.56 g). The XRPDpattern of this product is shown in FIG. 4.

(vi) Sulphanilate Salt

In a similar fashion, the title salt was prepared (0.52 g). The XRPDpattern of this product is shown in FIG. 5. M Pt 117° C.-123° C. δ(MeOH-d₄) 7.65 (1H, s), 7.62 (1H, d, J 7 Hz), 7.45 (2H, m), 7.35 (2H,m), 7.25 (1H, s), 7.05 (1H, d, J 7 Hz), 6.7 (1H, d, J 8 Hz), 6.55 (2H,d, J 8 Hz), 4.9 (m), 4.55 (2H, s), 3.33 (4H, m), 3.05 (2H, m), 2.95 (2H,t, J 8 Hz), 2.65 (2H, t, J 8 Hz), 1.8 (2H, m), 1.6 (2H, m), 1.48 (2H,m), 1.3 (6H, br s)

Example 49N²-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}glycinamideacetate i)N²-[(3-Iodophenyl)sulfonyl]-N²-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide

N²-[(3-Iodophenyl)sulfonyl]glycinamide (0.14 g) was stirred with sodiumhydride (60% oil dispersion, 0.02 g) in DMF (2 ml) at 21° under nitrogenfor 15 min. 2-Trimethylsilylethoxymethyl chloride (0.08 ml) was addedand stirring was continued for 1.5 h. The mixture was poured into pH 6.4phosphate buffer and the product was extracted three times with ethylacetate. The combined organic layers were washed with brine, dried(MgSO₄), concentrated and applied to a silica Bond Elut Cartridge (5 g)in dichloromethane containing methanol. The cartridge was eluted withdichloromethane, diethyl ether and ethyl acetate to give the titlecompound (0.16 g), LCMS RT=3.49 min.

ii)N²-[(3-{4-[(6-Iodohexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N²-{[2-(trimethylsilyl)ethoxy]methyl}glycinamidecompound withN²-[(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N-2-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide(55:45)

N²-[(3-Iodophenyl)sulfonyl]-N²-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide(0.16 g) was stirred with 6-bromohexyl but-3-ynyl ether (0.086 g) inacetonitrile (2 ml) and diisopropylethylamine (2 ml) under nitrogen for10 min. Cuprous iodide (0.01 g) anddichlorobis(triphenylphosphine)palladium (0.02 g) were added and thestirring continued for 2 h. The solution was evaporated to dryness andapplied to a Bond Elut cartridge (5 g) in dichloromethane. The cartridgewas eluted with dichloromethane and diethyl ether to give the titlecompounds (0.165 g), LCMS RT 3.93 min (bromide) and 4.02 min (iodide).

ii) 2-Azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone

2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (Glaxo DE3513885, 1985) (52 g) in DMF (300 ml) was treated with sodium azide(12.24 g) and the mixture was stirred for 2 h at 20° C. The reactionmixture was diluted with ethyl acetate and washed with water and dried(MgSO₄). The solvent was removed under reduced pressure to give thetitle compound (39.11 g). TSP+ve 248(MH)⁺.

iii) (1R)-2-Azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

R-(+)-2-Methyl-CBS-oxazaborolidine solution in toluene (1M, 7.5 ml) wasadded to THF (75 ml) and the solution was diluted to 0° C. Borane-THFcomplex (1M solution in THF, 125 ml) was added and the mixture wasstirred under nitrogen for 15 min. A solution of2-azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (24.7 g) in THF(250 ml) was added dropwise over 1.5 h at 5° C. The mixture was stirredfor a further 1 h and then cautiously treated with 2M HCl (100 ml). Thereaction mixture was extracted with ether and the organic layer waswashed with 2M HCl, NaHCO₃, brine, dried (MgSO₄). The solvent wasremoved by evaporation and the residue was chromatographed on a Biotagecolumn eluting with diethyl ether-petrol (40-60° C.) (1:9; 1:1) to givethe title compound (16.99 g). ES+ve 250 (MH)⁺.

iv) (1R)-2-Amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

(1R)-2-Azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (16.99 g)was hydrogenated over 10% Pd—C (1 g) in ethanol (300 ml). The catalystwas collected by filtration, and washed with ethanol. The combinedwashings were evaporated under reduced pressure and the residue wastriturated in diethyl ether to give the title compound (5.86 g). Themother liquors were chromatographed on a Biotage column eluting withtoluene:ethanol:aqueous ammonia (85:14:1) to give a further batch of thetitle compound (5.99 g). LCMS RT=1.68 min, ES+ve 206 (MH-H₂O)⁺.

vi)N²-[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N²-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide

(1R)-2-Amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (0.134 g)was stirred withN²-[(3-{4-[(6-iodohexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N²-{[2-(trimethylsilyl)ethoxy]methyl}glycinamidecompound withN²-[(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N²-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide(55:45) (0.165 g) in DMF (3 ml) for 4 days at 21°. The mixture wasevaporated to dryness and applied to a silica Bond Elut Cartridge (5 g)in ethyl acetate. This was eluted with ethyl acetate and then 10%methanol in ethyl acetate to give the title compound (0.081 g) LCMSRT=3.04 min.

vii)N²-[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]-N²-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide

N²[(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)sulfonyl]-N²-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide(0.09 g) was stirred with platinum oxide (0.023 g) in ethanol (20 ml)under hydrogen for 3.5 h. The catalyst was filtered off with the aid ofcelite and the filter cake was leached with ethanol. The combinedfiltrates were evaporated to give the title compound (0.091 g) LCMSRT=3.10 min.

viii)N²-{[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]sulfonyl}glycinamideacetate

N²-[(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)sulfonyl]-N²-{[2-(trimethylsilyl)ethoxy]methyl}glycinamide(0.091 g) was stirred under a reflux condenser at 80° in acetic acid (2ml) and water (1 ml) for 3.5 h. The solution was evaporated to drynessand re-evaporated twice with methanol to give a gum. The residue wasdissolved in methanol and loaded onto two 20×20 cm preparative silicagel coated plates (1 mm layer). The plates were run indichloromethane:ethanol:0.880 ammonia solution, 25:8:1 and elution ofthe main band and evaporation gave a gum. This was dissolved in aceticacid (2 ml) and evaporated to dryness and re-evaporated with methanol togive the title compound (0.019 g) LCMS RT=2.31 min, ES+ve 552 (MH)⁺.

Example 506α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester Unsolvated Form 1 (a)6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid

A solution of6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid (prepared in accordance with the procedure described in GB2088877B) (18 g, 43.64 mmol) in anhydrous dichloromethane (200 ml) andtriethylamine (15.94 ml, 114 mmol) was treated at <5° C. with a solutionof 2-furoyl chloride (11.24 ml, 114 mmol) in anhydrous dichloromethane(100 ml) over approximately 40 min. The solution was stirred at <5° C.for 30 min. The resulting solid was collected by filtration, washedsuccessively with 3.5% aqueous sodium hydrogen carbonate solution,water, 1M hydrochloric acid, and water and dried in vacuo at 60° C. togive a cream coloured solid. The dichloromethane filtrate was washedsuccessively with 3.5% sodium hydrogen carbonate solution, water, 1Mhydrochloric acid, water, dried (Na₂SO₄) and evaporated to give a creamcoloured solid which was combined with that isolated above. The combinedsolids (26.9 g) were suspended in acetone (450 ml) and stirred.Diethylamine (16.8 ml, 162 mmol) was added and the mixture stirred atroom temperature for 4.5 h. The mixture was concentrated and theprecipitate collected by filtration and washed with a little acetone.The washings and filtrate were combined, concentrated and loaded onto asilica gel Biotage column which was eluted with 24:1chloroform:methanol. Fractions which contained the more polar componentwere combined and evaporated to give a cream coloured solid. This wascombined with the solid isolated above and dried in vacuo to give a palebeige coloured solid (19.7 g). This was dissolved in warm water, the pHadjusted to 2 with concentrated hydrochloric acid and the mixtureextracted with ethyl acetate. The organic extract was dried (Na₂SO₄) andevaporated to give, after drying at 50° C., the title compound as acream coloured solid (18.081 g, 82%): LCMS retention time 3.88 min, m/z507 MH⁺, NMR δ (CDCl₃) includes 7.61 (1H, m), 7.18-7.12 (2H, m), 6.52(1H, dd, J 4, 2 Hz), 6.46 (1H, s), 6.41 (1H, dd, J 10, 2 Hz), 5.47 and5.35 (1H, 2m), 4.47 (1H, bd, J 9 Hz), 3.37 (1H, m), 1.55 (3H, s), 1.21(3H, s), 1.06 (3H, d, J 7 Hz).

A suspension of the product of part (a) (2.5 g, 4.94 mmol) was dissolvedin anhydrous N,N-dimethylformamide (25 ml) and sodium hydrogen carbonate(465 mg, 5.53 mmol) was added. The mixture was stirred at −20° C. andbromofluoromethane (0.77 ml, 6.37 mmol) was added and the mixture wasstirred at −20° C. for 2 h. Diethylamine (2.57 ml, 24.7 mmole) was addedand the mixture stirred at −20° C. for 30 min. The mixture was added to2M hydrochloric acid (93 ml) and stirred for 30 min. Water (300 ml) wasadded and the precipitate was collected by filtration, washed with waterand dried in vacuo at 50° C. to give a white solid which wasrecrystallised from acetone/water (to yield the acetone solvate of6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester) and dried in vacuo at 50° C. to give thetitle compound (2.351 g, 88%): LCMS retention time 3.66 min, m/z 539MH⁺, NMR δ (CDCl₃) includes 7.60 (1H, m), 7.18-7.11 (2H, m), 6.52 (1H,dd, J 4.2 Hz), 6.46 (1H, s), 6.41 (1H, dd, J 10, 2 Hz), 5.95 and 5.82(2H dd, J 51, 9 Hz), 5.48 and 5.35 (1H, 2m), 4.48 (1H, m), 3.48 (1H, m),1.55 (3H, s), 1.16 (3H, s), 1.06 (3H, d, J 7 Hz).

Example 516α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

Example 51 was prepared using a method analogous to that described forExample 50: LCMS retention time 3.51 min, m/z 570 MH⁺

Biological Activity

The potencies of the aforementioned compounds were determined using frogmelanophores transfected with the human beta 2 adrenoreceptor. The cellswere incubated with melatonin to induce pigment aggregation. Pigmentdispersal was induced by compounds acting on the human beta 2adrenoreceptor. The beta 2 agonist activity of test compounds wasassessed by their ability to induce a change in light transmittanceacross a melanophore monolayer (a consequence of pigment dispersal). Atthe human beta 2 adrenoreceptor, compounds of examples 1-49 had IC₅₀values below 1 μM.

Potency at other beta adrenoreceptor subtypes was determined usingchinese hamster ovary cells transfected with either the human beta 1adrenoreceptor or the human beta 3 adrenoreceptor. Agonist activity wasassessed by measuring changes in intracellular cyclic AMP.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1. A method for the treatment of a disease associated with reversibleairways obstruction selected from the group consisting of asthma,chronic obstructive pulmonary disease (COPD), respiratory tractinfection and upper respiratory tract disease, which comprisesadministrating a therapeutically effective amount of a compound offormula (I):

wherein: m is an integer of from 2 to 8; n is an integer of from 3 to11; with the proviso that m+n is 5 to 19; R¹ is —XSO₂NR⁶R⁷ wherein X is—(CH₂)_(p)— or C₂₋₆ alkenylene; R⁶ and R⁷ are independently selectedfrom hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, C(O)NR⁸R⁹, phenyl, andphenyl(C₁₋₄alkyl)-, or R⁶ and R⁷, together with the nitrogen to whichthey are bonded, form a 5-, 6-, or 7-membered nitrogen containing ring,and R⁶ and R⁷ are each optionally substituted by one or two groupsselected from halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,hydroxy-substituted C₁₋₆alkoxy, —CO₂R⁸, —SO₂NR⁸R⁹, —CONR⁸R⁹, —NR⁸C(O)R⁹,or a 5-, 6- or 7-membered heterocylic ring; R⁸ and R⁹ are independentlyselected from hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, andphenyl(C₁₋₄alkyl)-; and p is an integer of from 0 to 6; R² and R³ areindependently selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, halo,phenyl, and C₁₋₆haloalkyl; and R⁴ and R⁵ are independently selected fromhydrogen and C₁₋₄alkyl with the proviso that the total number of carbonatoms in R⁴ and R⁵ is not more than 4, or a pharmaceutically acceptablesalt, or solvate thereof, to the mammal.
 2. A method according to claim1, wherein the mammal is a human.
 3. A method according to claim 1,wherein the group R¹ is attached to the meta-position relative to the—O—(CH₂)_(n)— link.
 4. A method according to claim 1, wherein the groupR¹ represents —SO₂NR⁶R⁷ wherein R⁶ and R⁷ are independently selectedfrom hydrogen and C₁₋₆alkyl.
 5. A method according to claim 1, whereinR¹ is —SO₂NH₂.
 6. A method according to claim 1, wherein R⁴ and R⁵ areboth hydrogen.
 7. A method according to claim 1, wherein m is 5 or 6 andn is 3 or 4 such that m+n is 8, 9 or
 10. 8. A method according to claim1, wherein the compound of formula (I) is3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide;or a salt, or solvate thereof.
 9. A method according to claim 8, whereinthe compound is in the form of a salt formed with a pharmaceuticallyacceptable acid selected from cinnamic, substituted cinnamic,triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic, benzoic,4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and4-phenylbenzoic acid.
 10. A method according to claim 8, wherein thecompound of formula (I) is3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide4-phenylbenzoate.
 11. A method according to claim 8, wherein thecompound of formula (I) is3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamidetriphenylacetate.
 12. A method according to claim 8, wherein thecompound of formula (I) is3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide4-phenylcinnamate.
 13. A method according to claim 8, wherein thecompound of formula (I) is3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamidesulphamate.
 14. A method according to claim 8, wherein the compound offormula (I) is3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamidesulphanilate.
 15. A method according to claim 1, wherein the compound offormula (I) is3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzenesulfonamide;or a salt, or a solvate thereof.
 16. A method according to claim 15,wherein the compound is in the form of a salt formed with apharmaceutically acceptable acid selected from cinnamic, substitutedcinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic,benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and4-phenylbenzoic acid.
 17. A method according to claim 15, wherein thecompound of formula (I) is3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide1-hydroxynaphthoate.
 18. A method according to claim 15, wherein thecompound of formula (I) is3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide4-phenylbenzoate.
 19. A method according to claim 15, wherein thecompound of formula (I) is3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamidetriphenylacetate.
 20. A method according to claim 15, wherein thecompound of formula (I) is3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide4-methylcinnamate.
 21. A method according to claim 15, wherein thecompound of formula (I) is3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide4-methoxycinnamate.
 22. A method according to claim 15, wherein thecompound of formula (I) is3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide3-(2-naphthalenyl)-2-propanoate salt.
 23. A method according to claim 1,wherein the compound of formula (I) is3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide;or a salt, or solvate thereof.
 24. A method according to claim 1,wherein the compound of formula (I) is3-(4-{[6-({(2R/S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)benzenesulfonamide;or a salt, or solvate thereof.
 25. A method according to claim 1,wherein the compound of formula (I) is3-(3-{[7-({(2S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide;or a salt, or solvate thereof.
 26. A method according to claim 1,wherein the compound of formula (I) is3-(3-{[7-({(2R/S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)benzenesulfonamide;or a salt, or solvate thereof.
 27. A method according to claim 1,wherein the compound of formula (I) is in the form of a salt formed withan acid selected from the group consisting of cinnamic, substitutedcinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic,benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and4-phenylbenzoic acid.
 28. A method for the treatment of a diseaseassociated with reversible airways obstruction selected from the groupconsisting of asthma, chronic obstructive pulmonary disease (COPD),respiratory tract infection and upper respiratory tract disease, whichcomprises administrating a therapeutically effective amount of acompound of formula (Ia):

wherein R¹ is —XSO₂NR⁶R⁷ wherein X is —(CH₂)_(p)— or C₂₋₆ alkenylene; R⁶and R⁷ are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C(O)NR⁸R⁹, phenyl, and phenyl(C₁₋₄alkyl)-, or R⁶ and R⁷,together with the nitrogen to which they are bonded, form a 5-, 6-, or7-membered nitrogen containing ring, and R⁶ and R⁷ are each optionallysubstituted by one or two groups selected from halo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, hydroxy-substituted C₁₋₆alkoxy, —CO₂R⁸,—SO₂NR⁸R⁹, —CONR⁸R⁹, —NR⁸C(O)R⁹, or a 5-, 6- or 7-membered heterocylicring; R⁸ and R⁹ are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₆cycloalkyl, phenyl, and phenyl(C₁₋₄alkyl)-; and p is an integer offrom 0 to 6; or a pharmaceutically acceptable salt, or solvate thereof,to the mammal.
 29. A method for the treatment of a disease associatedwith reversible airways obstruction selected from the group consistingof asthma, chronic obstructive pulmonary disease (COPD), respiratorytract infection and upper respiratory tract disease, which comprisesadministrating a therapeutically effective amount of a compound offormula (Ib):

or a salt, solvate, or physiologically functional derivative thereof,wherein R¹ is —XSO₂NR⁶R⁷ wherein X is —(CH₂)_(p)— or C₂₋₆ alkenylene; R⁶and R⁷ are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C(O)NR⁸R⁹, phenyl, and phenyl(C₁₋₄alkyl)-, or R⁶ and R⁷,together with the nitrogen to which they are bonded, form a 5-, 6-, or7-membered nitrogen containing ring, and R⁶ and R⁷ are each optionallysubstituted by one or two groups selected from halo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, hydroxy-substituted C₁₋₆alkoxy, —CO₂R⁸,—SO₂NR⁸R⁹, —CONR⁸R⁹, —NR⁸C(O)R⁹, or a 5-, 6- or 7-membered heterocylicring; R⁸ and R⁹ are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₆cycloalkyl, phenyl, and phenyl(C₁₋₄alkyl)-; and p is an integer offrom 0 to 6; or a pharmaceutically acceptable salt, or solvate thereof,to the mammal.